Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more traditional review articles on these and also on surrounding topics ("deep insights"), case reports in hematology, and educational items in the various related topics for students in Medicine and in Sciences.
Editorial correspondance
Jean-Loup Huret Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France tel +33 5 49 44 45 46 or +33 5 49 45 47 67 [email protected] or [email protected]
Staff Mohammad Ahmad, Mélanie Arsaban, Mikael Cordon, Isabelle Dabin, Marie-Christine Jacquemot-Perbal, Maureen Labarussias, Anne Malo, Catherine Morel-Pair, Laurent Rassinoux, Sylvie Yau Chun Wan - Senon, Alain Zasadzinski. Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy Institute – Villejuif – France).
The Atlas of Genetics and Cytogenetics in Oncology and Haematology (ISSN 1768-3262) is published 12 times a year by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French National Center for Scientific Research (INIST-CNRS) since 2008. The Atlas is hosted by INIST-CNRS (http://www.inist.fr)
The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research (CNRS) on its electronic publishing platform I-Revues. Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS.
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more traditional review articles on these and also on surrounding topics ("deep insights"), case reports in hematology, and educational items in the various related topics for students in Medicine and in Sciences.
Editorial correspondance
Jean-Loup Huret Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France tel +33 5 49 44 45 46 or +33 5 49 45 47 67 [email protected] or [email protected]
Staff Mohammad Ahmad, Mélanie Arsaban, Mikael Cordon, Isabelle Dabin, Marie-Christine Jacquemot-Perbal, Maureen Labarussias, Anne Malo, Catherine Morel-Pair, Laurent Rassinoux, Sylvie Yau Chun Wan - Senon, Alain Zasadzinski. Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy Institute – Villejuif – France).
The Atlas of Genetics and Cytogenetics in Oncology and Haematology (ISSN 1768-3262) is published 12 times a year by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French National Center for Scientific Research (INIST-CNRS) since 2008. The Atlas is hosted by INIST-CNRS (http://www.inist.fr)
Local order: According to the NCBI map viewer, genes flanking BOP1, in centromere to telomere direction on 8q24.3, are: GPAA1, 8q24.3, glycosylphosphatidylinositol anchor attachment protein 1 homolog (yeast); CYC1, 8q24.3, cytochrome c-1; SHARPIN, 8q24.3, SHANK-associated RH domain interactor; MAF1, 8q24.3, MAF1 homolog (S. cerevisiae); KIAA1875, 8q24.3; C8orf30A, 8q24.3, chromosome 8 open reading frame 30A; KIAA1833, 8q24.3, hypothetical protein KIAA1833; BOP1, 8q24.3, block of proliferation 1; HSF1, 8q24.3, heat shock transcription factor 1;
DGAT1, 8q24.3, diacylglycerol O-acyltransferase homolog 1 (mouse); FBXL6, 8q24.3, F-box and leucine-rich repeat protein 6; GPR172A, 8q24.3, G protein-coupled receptor 172A; ADCK5, 8q24.3, aarF domain containing kinase 5; CPSF1, 8q24.3, cleavage and polyadenylation specific factor 1, 160kDa; SLC39A4, 8q24.3, solute carrier family 39 (zinc transporter), member 4. Note: The BOP1 gene is a member of the nucleolar PeBoW-complex (PES1, BOP1, WDR12) essential for cell proliferation and maturation of the large ribosomal subunit. On the basis of experiments performed in yeast, this complex is likely to involve other proteins: GRWD1, RPL3, and ORC6L. A better designation, found in some databases, should be: ribosome biogenesis protein BOP1.
Fig1 A: Genomic structure of BOP1: the gene extends over 29kb with 16 exons (lower part). Exons 4-16 (upper part) are clustered in 2.6 kb while exons 1-3 are separated by large (2-12 kb) introns.
BOP1 (block of proliferation 1) Killian A, Sesboüé R
DNA/RNA Description The BOP1 gene is situated 16.6 Mb downstream from the MYC proto-oncogene (8q24.21) and 0.8 Mb upstream from the telomere (Fig1B).
Transcription BOP1 mRNA (NM_015201) has a size of 2422 bp.
Pseudogene No pseudogene has been reported for BOP1, but the NCBI Map viewer (Build 36.3) displays a perfect match encompassing exons 4-16, 64kb centromeric to the gene.
Protein Description The Ribosome biogenesis protein BOP1 consists of 746 amino acids and has a molecular weight of 83.63 kDa. It contains 7 WD repeats.
Expression BOP1 is expressed ubiquitously and found in nearly all tissues at similar levels.
Localisation Nucleus, nucleolus.
Function Required for maturation of the 25S and 5.8S ribosomal RNAs. Essential for cell proliferation. Involved in chromosomal segregation.
Implicated in Colorectal cancer Note A copy number increase of the BOP1 gene was detected in 39% of colorectal cancer samples (n=56) and was associated with an increase of its mRNA level. This copy number increase was more frequent than that observed for MYC, a proto-oncogene located 16.6 Mb upstream from BOP1 and was distinct from MYC amplification in 16% of the cases. Transient overexpression of BOP1 in human cells increased the percentage of abnormal mitoses with multipolar spindles.
References Killian A, Le Meur N, Sesboüé R, Bourguignon J, et al. Inactivation of the RRB1-Pescadillo pathway involved in ribosome biogenesis induces chromosomal instability. Oncogene. 2004 Nov 11;23(53):8597-602
Hölzel M, Rohrmoser M, Schlee M, Grimm T, et al. Mammalian WDR12 is a novel member of the Pes1-Bop1 complex and is required for ribosome biogenesis and cell proliferation. J Cell Biol. 2005 Aug 1;170(3):367-78
Grimm T, Hölzel M, Rohrmoser M, Harasim T, et al. Dominant-negative Pes1 mutants inhibit ribosomal RNA processing and cell proliferation via incorporation into the PeBoW-complex. Nucleic Acids Res. 2006;34(10):3030-43
Killian A, Sarafan-Vasseur N, Sesboüé R, Le Pessot F, Blanchard F, Lamy A, Laurent M, Flaman JM, Frébourg T. Contribution of the BOP1 gene, located on 8q24, to colorectal tumorigenesis. Genes Chromosomes Cancer. 2006 Sep;45(9):874-81
Rohrmoser M, Hölzel M, Grimm T, Malamoussi A, et al. Interdependence of Pes1, Bop1, and WDR12 controls nucleolar localization and assembly of the PeBoW complex required for maturation of the 60S ribosomal subunit. Mol Cell Biol. 2007 May;27(10):3682-94
This article should be referenced as such:
Killian A, Sesboüé R. BOP1 (block of proliferation 1). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9):622-623.
DNA/RNA Description The GLTSCR2 gene comprises 13 exons resulting in a transcript of 1567 bases. The start codon is in the 1st exon; the stop codon is in the 13th exon. Northern blot analysis shows a 1.5-kb transcript.
Transcription mRNA: ubiquitously.
Pseudogene Not known.
Protein Description 478 amino acids. GLTSCR2 protein contains a putative PEST sequence (PEST score: +7.23, aa: 279-332) and a potential nuclear localization signal (aa: 378-386).
Localisation Nucleolus.
Function GLTSCR2 protein binds to PTEN tumor suppressor and regulates its stability in cells. Recent reports show the implication of GLTSCR2 in cell proliferation and apoptosis.
Homology GLTSCR2 orthologs can be found in metazoans. In addition, GLTSCR2 protein shares homology with yeast Nop53p which is involved in ribosome biogenesis.
Mutations Note There are several synonymous and nonsynonymous SNPs reported for GLTSCR2 (S16R, Q169E, C325F, A383V, Q389R).
Implicated in Cancer Note A number of groups have proven that the 19q13.32 locus where GLTSCR2 gene locates is frequently altered in glioma and neuroblastoma; however, a tumor suppressor gene(s) specifically encoded in this region has yet to be identified and the implication of GLTSCR2 gene in these tumors remains controversial. Recent studies show aberrations in GLTSCR2 expression in glioblastoma and neuroblastoma.
References Smith JS, Tachibana I, Pohl U, Lee HK, Thanarajasingam U, Portier BP, Ueki K, Ramaswamy S, Billings SJ, Mohrenweiser HW, Louis DN, Jenkins RB. A transcript map of the chromosome 19q-arm glioma tumor suppressor region. Genomics. 2000 Feb 15;64(1):44-50
Mora J, Cheung NK, Chen L, Qin J, Gerald W. Loss of heterozygosity at 19q13.3 is associated with locally aggressive neuroblastoma. Clin Cancer Res. 2001 May;7(5):1358-61
GLTSCR2 (glioma tumor suppressor candidate region gene 2) Maehama T
Hartmann C, Johnk L, Kitange G, Wu Y, Ashworth LK, Jenkins RB, Louis DN. Transcript map of the 3.7-Mb D19S112-D19S246 candidate tumor suppressor region on the long arm of chromosome 19. Cancer Res. 2002 Jul 15;62(14):4100-8
Maehama T, Okahara F, Kanaho Y. The tumour suppressor PTEN: involvement of a tumour suppressor candidate protein in PTEN turnover. Biochem Soc Trans. 2004 Apr;32(Pt 2):343-7
Okahara F, Ikawa H, Kanaho Y, Maehama T. Regulation of PTEN phosphorylation and stability by a tumor suppressor candidate protein. J Biol Chem. 2004 Oct 29;279(44):45300-3
Okahara F, Itoh K, Nakagawara A, Murakami M, Kanaho Y, Maehama T. Critical role of PICT-1, a tumor suppressor candidate, in phosphatidylinositol 3,4,5-trisphosphate signals and tumorigenic transformation. Mol Biol Cell. 2006 Nov;17(11):4888-95
Ji D, Deeds SL, Weinstein EJ. A screen of shRNAs targeting tumor suppressor genes to identify factors involved in A549 paclitaxel sensitivity. Oncol Rep. 2007 Dec;18(6):1499-505
Yim JH, Kim YJ, Cho YE, Ko JH, Kim SM, Kim JY, Park JH. GLTSCR2 sensitizes cells to hypoxic injury without involvement of mitochondrial apoptotic cascades. Pathobiology. 2007;74(5):301-8
Yim JH, Kim YJ, Ko JH, Cho YE, Kim SM, Kim JY, Lee S, Park JH. The putative tumor suppressor gene GLTSCR2 induces PTEN-modulated cell death. Cell Death Differ. 2007 Nov;14(11):1872-9
Kim YJ, Cho YE, Kim YW, Kim JY, Lee S, Park JH. Suppression of putative tumour suppressor gene GLTSCR2 expression in human glioblastomas. J Pathol. 2008 Oct;216(2):218-24
This article should be referenced as such:
Maehama T. GLTSCR2 (glioma tumor suppressor candidate region gene 2). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9):624-625.
Identity Other names: HSPG, PLC, PRCAN, Perlecan, SJA, SJS, SJS1
HGNC (Hugo): HSPG2
Location: 1p36.12
DNA/RNA Description The HSPG2 gene consists of 115,014 bases and 97 exons. Evidence suggests that the encoded protein's modular structure is a result of gene duplication and exon shuffling (Cohen et al., 1993). The perlecan gene promoter lacks the TATA and CAAT boxes, but has
four GC boxes and three GGGCGG hexanucleotides. The gene also was found to contain multiple start sites (Cohen et al., 1993).
Transcription The transcribed mRNA is 14,294 bp (Cohen et al., 1993). An alternative transcript for unc-52, the homologous gene to perlecan in C. elegans, has been reported (Spike et al., 2002). In addition, a human alternative transcript was submitted to the NCBI (Accession Q8TEU3_HUMAN) as a sequence for a short version variant, miniperl, encoding a 240 amino acid protein of 25.942 kD. Expression of HSPG2 was found to be induced by TGF-beta via NF-1 (Iozzo et al., 1997), and inhibited by NF-gamma via STAT1 (Sharma and Iozzo, 1998).
Protein
Figure1: Perlecan as a Scaffold: Functional Uncoupling by Proteolysis (from Farach-Carson and Carson, 2007).
HSPG2 (heparan sulfate proteoglycan 2) Farach-Carson MC, Grindel B
Description 4,391 amino acids; 468,825 (core protein) to ~850,000 Da (depends upon amount of glycosaminoglycan (GAG) additions). Perlecan is composed of 5 domains. Following a 21 amino acid signal peptide for ER targeting is the N-terminal domain I, spanning amino acids 22-193 (Murdoch et al., 1992). Domain I contains 3 SGD sequences for attachment of heparan sulfate (HS) and/or chondroitin sulfate (CS) GAGs on serine residues, and a 120 amino acid SEA (Sperm protein, Enterokinase, Agrin) module. The SEA module has no definitive function, but deletion studies in domain I suggest it increases HS chain attachment (Dolan et al., 1997). Domain I of this protein is unique to perlecan, as it shares no significant homology with any other protein (Murdoch et al., 1992). The 210 amino acid domain II (amino acids 194-403) contains 4 cysteine-rich low-density lipoprotein (LDL) receptor-like modules. Adjacent to this is one immunoglobulin G (IgG)-like repeat (residues 404-504). Domain III (1,172 amino acids; residues 505-1676) consists of modules homologous to the short arm laminin alpha-chains including 3 laminin domain IV-like modules and eight laminin epidermal growth factor (EGF)-like repeats. Domain IV is the largest domain (2010 amino acids; residues 1677-3686), containing 21 IgG-like repeats (murine perlecan has only 14 IgG-like repeats, missing IgG repeats 5-12) similar to neural cell adhesion molecules (N-CAM). Domain V (705 amino acids; residues 3687-4391) has 3 modules with sequence homology to the globular domain of laminin alpha-chains and agrin. In addition, this domain contains 4 interspersed EGF-like repeats, and another GAG chain attachment site. Domain V of perlecan also is referred to as endorepellin for its angiostatic properties and was shown to be cleaved from perlecan by BMP-1/mTLL (Mongiat et al., 2003; Gonzalez et al., 2005). Several other cleavage sites are predicted for perlecan including sites for thrombin, plasmin, collagenase, and
stromelysin, although some sites may be cryptic (Whitelock et al., 1996; d'Ortho et al., 1997).
Expression Perlecan is expressed in the basement membranes of pituitary gland, skin, breast, thymus, prostate, colon, liver, pancreas, spleen, heart, and lung. Vascular basement membranes also express perlecan. In the subendothelial region, perlecan is highly expressed in the liver's perisinusoidal space, spleen, lymph nodes, and pituitary gland (Murdoch et al., 1994). In the kidney, perlecan is found in the mesangium, Bowman's capsule, the tubular basement membrane, but is only slightly expressed in the glomerular basement membrane (Groffen et al., 1997). In bone, marrow but not the mineral compartment, is rich in perlecan (Schofield et al., 1999). In human fetal tissue (12-14 week old), pericellular perlecan expression was detected in the rudiment and growth plate chondrocytes, and was found in the perichondrial capillary networks and cartilage canals (Melrose et al., 2004).
Localisation Perlecan is found in the extracellular matrix (ECM), most commonly in the basement membrane underlying epithelial and endothelial cells. It also is found at high levels in cartilage, bone marrow and in muscle tissue.
Function Perlecan is a multifunctional protein involved in maintaining the basement membrane, growth factor binding and signaling, cell differentiation, angiogenesis, neuromuscular function and bone development. Perlecan is an important component of the basement membrane. It binds several other basement membrane proteins including aminin 1, fibronectin, nidogen, PRELP, and collagen IV via its core protein or HS chains (Sasaki et al., 1998; Hopf et al., 2001; Kvansakul et al., 2001; Bengtsson et al., 2002).
Figure 2: from Farach-Carson and Carson, 2007.
HSPG2 (heparan sulfate proteoglycan 2) Farach-Carson MC, Grindel B
Figure 3: Perlecan as a Scaffold: Domains and interactions (from Farach-Carson and Carson, 2007).
Endorepellin (domain V) also interacts with cell surface integrins (alpha2beta1), forming additional complexes linking the ECM with the cell (Bix et al., 2004). The loss of perlecan and the basement membrane architecture is sometimes indicative of carcinomas, as is the case with invasive breast carcinoma (Nerlich et al., 1997). Perlecan has extensive growth factor regulating functions afforded to its ability to bind, sequester, and activate growth factors and growth factor binding proteins. This function connects perlecan to several actions concerning cell differentiation and proliferation. Perlecan has both pro-angiogenic (whole molecule) and anti-angiogenic (endorepellin) properties, linked to its ability regulate factors such as VEGF and FGF2. Consequently, perlecan has been implicated in supporting tumor angiogenesis in several cancers (reviewed in Bix and Iozzo, 2008). In all, perlecan has been shown to bind many growth factors including BMP-2, CTGF, PDGF, several FGFs, and VEGF and modulate several others (reviewed in Bix and Iozzo, 2008; Melrose et al., 2008). Perlecan has important functions in bone development. Perlecan sustains growth plate chondrocyte organization and hypertrophic chondrocytes, greatly assists endochondral ossification, and maintains cartilage stability in general (Arikawa-Hirasawa et al., 1999; Costell et al., 1999). The
complex structure and function of perlecan suggest that it acts as an extracellular matrix scaffold. Based upon rotary shadowing of individual domains and atomic force microscopy, intact perlecan is predicted to span 100-200 nm (Chakravarti et al., 1995; Costell et al., 1996; Brown et al., 1997; Dolan et al., 1997; Hopf et al., 1999; Chen and Hansma, 2000). Given that this matches the dimensions of other scaffolding domains and that perlecan has a modular structure capable of binding many partners at once, perlecan may create stable "signalosomes" by clustering transmembrane proteins and stabilizing their interactions. As a result, perlecan may be essential in directing cell signaling and hence function as an extracellular signaling scaffold (Farach-Carson and Carson, 2007).
Mutations Note Perlecan has 37 reported mutations. Over 34 mutations are attributed to Schwartz-Jampel Syndrome (SJS) and 3 are attributed to dyssegmental dysplasia, Silverman-Handmaker type (DDHS).
HSPG2 (heparan sulfate proteoglycan 2) Farach-Carson MC, Grindel B
Implicated in Prostate Cancer Note Perlecan expression was correlated with aggressive prostate tumors (high Gleason score). Primary prostate cancer tumors and metastatic prostate cancer to the lung and liver showed increased perlecan expression, but metastasis to the lymph nodes showed decreased perlecan protein expression. Furthermore, perlecan expression was shown to promote survival of tumors in low androgen and/or low growth factor environments. Perlecan may mediate prostate cancer progression through its regulation of the sonic hedgehog signaling pathway, whose activity has been implicated in prostate cancer (Datta et al., 2006). Targeted reduction of perlecan in prostate cancer xenografts growing in mice reduced tumor growth and vascularization (Savorè et al., 2005).
Disease Prostate cancer is an adenocarcimona affecting the gland cells of the prostate. It is a slow growing cancer
usually affecting older men. The most common site of metastasis of prostate cancer is the bone.
Breast Cancer Note Perlecan mRNA expression was shown to be increased in invasive breast carcinomas, yet immunohistochemical analysis showed a lack of perlecan deposition in the carcinoma (Nerlich et al., 1997; Nerlich et al., 1998). This suggests subsequent proteolytic cleavage of perlecan or translational defects in breast cancer. However, in breast cancer stromal cells, high perlecan deposition was also reported (Iozzo et al., 1994).
Disease Breast cancer refers to the many types of cancer affecting breast tissue including ductal carcinoma and lobular carcinoma. Breast cancers are further defined as in situ or invasive. An especially deadly form is inflammatory breast cancer. The most common target of breast cancer metastasis is the lymphatic system. It is the most common form of cancer for women and the second cause of cancer-related deaths for women.
HSPG2 (heparan sulfate proteoglycan 2) Farach-Carson MC, Grindel B
Prognosis None. Melanoma Note In metastatic melanoma, perlecan mRNA expression was increased 15 fold over normal tissue, which correlated with enhanced perlecan deposition in the melanoma's pericellular matrix (Cohen et al., 1994). When perlecan expression was blocked with a perlecan antisense cDNA construct in metastatic melanoma cells, the proliferative and invasive properties were reduced. Perlecan serves as a reservoir for growth factors involved in angiogenesis and proliferation (VEGF, bFGF/FGF-2, FGF-7), and is needed for growth factor signaling. bFGF/FGF-2 was shown to be an important autocrine regulator of metastatic melanoma, and perlecan is needed for bFGF to advance melanoma. Without perlecan, growth factor activity is diminished, abrogating tumor progression (Adatia et al., 1997).
Disease Melanoma is a type of skin cancer originating in the melanocytes.
Prognosis None.
Colon cancer Note When perlecan was blocked by antisense targeting in xenografts with human colon carcinoma cells and tumor allografts, tumor progression and neovascularization were substantially decreased in a mouse model. Perlecan inhibition is thought to suppress FGF-7 binding and receptor activation, thereby blocking tumor growth and angiogenesis (Sharma et al., 1998). As in other cancers, perlecan is a contributing factor in colon cancer progression.
Disease Colon cancer usually begins as a non-cancerous adenomatous polyp and spreads into the wall of the colon, where it may metastasize through blood vessels or the lymphatic system.
Prognosis None.
Fibrosarcoma Note In contrast to other cancers, when perlecan was suppressed by antisense cDNA in fibrosarcoma cells, the phenotype became more aggressive in that they had increased migration, invasion, and adhesiveness to type IV collagen substrates. Perlecan action in fibrosarcoma is thought to be independent of the bFGF pathway and possibly prevent mesenchymal tumor invasion (Mathiak et al., 1997).
Disease Fibrosarcoma is a type of malignant tumor originating in the connective tissue, mostly affecting the leg, arm, and jawbone in humans.
Prognosis None.
Adenoid cystic carcinoma (ACC) Note Perlecan expression was increased in ACC cells forming small stromal pseudocysts, but not in advanced flat ACC cells producing large pseudocysts or already attached to peripheral nerves, which have abundant perlecan. This suggests perlecan is needed for initial ACC cell growth (Kimura et al., 2000).
Disease ACC is a tumor affecting the salivary glands. It is usually slow growing and not as aggressive as other salivary gland cancers.
Prognosis None.
Intrahepatic cholangiocarcinoma (ICC) Note Perlecan is highly expressed in the tumor specific fibro-myxoid stroma of ICC. In addition, the ICC cells on the invading fronts expressed higher levels of perlecan than other ICC cells, suggesting that perlecan is an important component of ICC tumor invasiveness (Sabit et al., 2001).
Disease ICC is a tumor originating in the biliary system (bile ducts) of the liver. It is associated with the hepatitis C virus and chronic cholangitis.
Prognosis None.
Amyloidosis and related diseases Note In a murine model of AA amyloidogenesis perlecan expression increased before the deposits of AA amyloids, indicating that perlecan is required for the earliest stages of amyloid fibrillogenesis (Ailles et al., 1993). Perlecan was shown to accelerate beta-amyloid fibril formation and also stabilize the formed fibrils, demonstrating perlecan's role in beta-amyloidogenesis in Alzheimer's disease (Castillo et al., 1997). In addition, during hemodialysis induced beta2-microglobulin (beta2M) amyloidosis, increased amounts of HSPGs, like perlecan, direct where beta2M deposits will occur and assist fibrillogenesis (Ohashi, 2001).
Disease Amyloidosis refers to a wide spectrum of diseases where the abnormal deposition of amyloid species
HSPG2 (heparan sulfate proteoglycan 2) Farach-Carson MC, Grindel B
(insoluble proteins in a beta-pleated secondary conformation) occurs in any organ or tissue. Alzheimer's disease is an example of amyloidosis affecting the brain.
Prognosis None.
Schwartz-Jampel Syndrome (SJS) Note Mutations in the perlecan gene were implicated in SJS in 2000 by (Nicole et al., 2000). Two mutations are found in the C-terminal region of domain III, SJS1-H C1532Y and SJS1-B 4740G→A, resulting in lost disulfide bonds. One mutation was found in domain IV, SJS1-A IVS64+4a→g, leaving a truncated protein missing domain IV Ig-like repeats 13-21 and domain V. (Arikawa-Hirasawa et al., 2002) reported additional mutations resulting in early stop codons. (Stum et al., 2006) reported an additional 22 perlecan mutations. In all of these mutational analyses, no evidence of a founder effect existed. The mutated perlecan proteins are secreted in lower amounts or are more susceptible to proteases and have varying degrees of functionality, resulting in the defects characteristic of SJS. However, (Rodgers et al., 2007) using mice with site specific perlecan mutations suggested that it was not the truncated protein or faulty secretion, but a downregulation of perlecan at the transcriptional level. With respect to myotonia, perlecan was shown to localize acetylcholinesterase (AChE) to the neuromuscular junction. With less functional perlecan, AChE is largely absent at the synapse, resulting in a higher concentration of ACh. This aberrantly stimulates the ACh receptor causing muscle contractions associated with myotonia.
Disease SJS is a rare autosomal recessive disease characterized by skeletal dysplasias and myotonia, a neuromuscular disorder resulting in prolonged muscle contraction. Patients with the disorder have short stature, blepharophimosis (drooping eyelids with reduced size, flat nasal bridge, underdeveloped orbital rim), pursed lips, low-set ears, myopia, and a fixed facial expression. SJS is characterized by several skeletal dysplasias including kyphoscloliosis, platyspondyly (flattened vertebrae), joint contractures, and metaphyseal and epiphyseal dysplasias. Based upon clinical examination, several other disorders including kyphomelic chondrodyplasia, Burton's disease, micromelic chondrodysplasia were suggested by (Spranger et al., 2000) to be reclassified as SJS.
Dyssegmental dysplasia, Silverman-Handmaker type (DDHS) Note Functional null mutations of perlecan have been implicated in DDHS. (Arikawa-Hirasawa et al., 2001)
reported an 89-bp duplication in exon 34, and a 5' donor site mutation in intron 52 and exon 73, resulting in a truncated perlecan protein core. In contrast to SJS, the truncated perlecan protein is not secreted and deposited, causing a functional null mutation similar to the homozygous perlecan knockout mice. This manifests in more severe defects than SJS, as all DDHS individuals are stillbirths or die shortly thereafter.
Disease DDSH is a rare autosomal recessive lethal disease characterized by severe skeletal dysplasias, anisospondyly and micromelia. DDSH patients also have a flat face, cleft palate, low joint mobility, micrognathia (undersized jaw), and encephalocoele. The endochondral growth plate has shortening defects, the resting cartilage shows mucoid degeneration, and hypertrophic chondrocytes produce calcospherites that fail to fuse.
Intracranial aneurysms Note Two SNPs in the perlecan gene were associated with intracranial aneurysms (Ruigrok et al., 2006). A defect in perlecan is thought to contribute to faulty ECM in the arterial wall, increasing the likelihood of an aneurysm.
Disease An aneurysm is the dilation of the arterial wall due to defects in the ECM. A dilated blood vessel may rupture resulting in a subarachnoid hemorrhage.
References Murdoch AD, Dodge GR, Cohen I, Tuan RS, Iozzo RV. Primary structure of the human heparan sulfate proteoglycan from basement membrane (HSPG2/perlecan). A chimeric molecule with multiple domains homologous to the low density lipoprotein receptor, laminin, neural cell adhesion molecules, and epidermal growth factor. J Biol Chem. 1992 Apr 25;267(12):8544-57
Ailles L, Kisilevsky R, Young ID. Induction of perlecan gene expression precedes amyloid formation during experimental murine AA amyloidogenesis. Lab Invest. 1993 Oct;69(4):443-8
Cohen IR, Grässel S, Murdoch AD, Iozzo RV. Structural characterization of the complete human perlecan gene and its promoter. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10404-8
Cohen IR, Murdoch AD, Naso MF, Marchetti D, Berd D, Iozzo RV. Abnormal expression of perlecan proteoglycan in metastatic melanomas. Cancer Res. 1994 Nov 15;54(22):5771-4
Iozzo RV, Cohen IR, Grässel S, Murdoch AD. The biology of perlecan: the multifaceted heparan sulphate proteoglycan of basement membranes and pericellular matrices. Biochem J. 1994 Sep 15;302 ( Pt 3):625-39
Murdoch AD, Liu B, Schwarting R, Tuan RS, Iozzo RV. Widespread expression of perlecan proteoglycan in basement membranes and extracellular matrices of human tissues as detected by a novel monoclonal antibody against domain III and by in situ hybridization. J Histochem Cytochem. 1994 Feb;42(2):239-49
HSPG2 (heparan sulfate proteoglycan 2) Farach-Carson MC, Grindel B
Chakravarti S, Horchar T, Jefferson B, Laurie GW, Hassell JR. Recombinant domain III of perlecan promotes cell attachment through its RGDS sequence. J Biol Chem. 1995 Jan 6;270(1):404-9
Costell M, Sasaki T, Mann K, Yamada Y, Timpl R. Structural characterization of recombinant domain II of the basement membrane proteoglycan perlecan. FEBS Lett. 1996 Nov 4;396(2-3):127-31
Whitelock JM, Murdoch AD, Iozzo RV, Underwood PA. The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin, and heparanases. J Biol Chem. 1996 Apr 26;271(17):10079-86
Adatia R, Albini A, Carlone S, Giunciuglio D, Benelli R, Santi L, Noonan DM. Suppression of invasive behavior of melanoma cells by stable expression of anti-sense perlecan cDNA. Ann Oncol. 1997 Dec;8(12):1257-61
Brown JC, Sasaki T, Göhring W, Yamada Y, Timpl R. The C-terminal domain V of perlecan promotes beta1 integrin-mediated cell adhesion, binds heparin, nidogen and fibulin-2 and can be modified by glycosaminoglycans. Eur J Biochem. 1997 Nov 15;250(1):39-46
Castillo GM, Ngo C, Cummings J, Wight TN, Snow AD. Perlecan binds to the beta-amyloid proteins (A beta) of Alzheimer's disease, accelerates A beta fibril formation, and maintains A beta fibril stability. J Neurochem. 1997 Dec;69(6):2452-65
Dolan M, Horchar T, Rigatti B, Hassell JR. Identification of sites in domain I of perlecan that regulate heparan sulfate synthesis. J Biol Chem. 1997 Feb 14;272(7):4316-22
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Groffen AJ, Hop FW, Tryggvason K, Dijkman H, Assmann KJ, Veerkamp JH, Monnens LA, Van den Heuvel LP. Evidence for the existence of multiple heparan sulfate proteoglycans in the human glomerular basement membrane and mesangial matrix. Eur J Biochem. 1997 Jul 1;247(1):175-82
Iozzo RV, Pillarisetti J, Sharma B, Murdoch AD, Danielson KG, Uitto J, Mauviel A. Structural and functional characterization of the human perlecan gene promoter. Transcriptional activation by transforming growth factor-beta via a nuclear factor 1-binding element. J Biol Chem. 1997 Feb 21;272(8):5219-28
Mathiak M, Yenisey C, Grant DS, Sharma B, Iozzo RV. A role for perlecan in the suppression of growth and invasion in fibrosarcoma cells. Cancer Res. 1997 Jun 1;57(11):2130-6
Nerlich AG, Wiest I, Wagner E, Sauer U, Schleicher ED. Gene expression and protein deposition of major basement membrane components and TGF-beta 1 in human breast cancer. Anticancer Res. 1997 Nov-Dec;17(6D):4443-9
Nerlich AG, Lebeau A, Hagedorn HG, Sauer U, Schleicher ED. Morphological aspects of altered basement membrane metabolism in invasive carcinomas of the breast and the larynx. Anticancer Res. 1998 Sep-Oct;18(5A):3515-20
Sasaki T, Costell M, Mann K, Timpl R. Inhibition of glycosaminoglycan modification of perlecan domain I by site-directed mutagenesis changes protease sensitivity and laminin-1 binding activity. FEBS Lett. 1998 Sep 18;435(2-3):169-72
Sharma B, Handler M, Eichstetter I, Whitelock JM, Nugent MA, Iozzo RV. Antisense targeting of perlecan blocks tumor growth
and angiogenesis in vivo. J Clin Invest. 1998 Oct 15;102(8):1599-608
Sharma B, Iozzo RV. Transcriptional silencing of perlecan gene expression by interferon-gamma. J Biol Chem. 1998 Feb 20;273(8):4642-6
Arikawa-Hirasawa E, Watanabe H, Takami H, Hassell JR, Yamada Y. Perlecan is essential for cartilage and cephalic development. Nat Genet. 1999 Nov;23(3):354-8
Costell M, Gustafsson E, Aszódi A, Mörgelin M, Bloch W, Hunziker E, Addicks K, Timpl R, Fässler R. Perlecan maintains the integrity of cartilage and some basement membranes. J Cell Biol. 1999 Nov 29;147(5):1109-22
Hopf M, Göhring W, Kohfeldt E, Yamada Y, Timpl R. Recombinant domain IV of perlecan binds to nidogens, laminin-nidogen complex, fibronectin, fibulin-2 and heparin. Eur J Biochem. 1999 Feb;259(3):917-25
Schofield KP, Gallagher JT, David G. Expression of proteoglycan core proteins in human bone marrow stroma. Biochem J. 1999 Nov 1;343 Pt 3:663-8
Chen CH, Hansma HG. Basement membrane macromolecules: insights from atomic force microscopy. J Struct Biol. 2000 Jul;131(1):44-55
Kimura S, Cheng J, Ida H, Hao N, Fujimori Y, Saku T. Perlecan (heparan sulfate proteoglycan) gene expression reflected in the characteristic histological architecture of salivary adenoid cystic carcinoma. Virchows Arch. 2000 Aug;437(2):122-8
Nicole S, Davoine CS, Topaloglu H, Cattolico L, Barral D, Beighton P, Hamida CB, Hammouda H, Cruaud C, White PS, Samson D, Urtizberea JA, Lehmann-Horn F, Weissenbach J, Hentati F, Fontaine B. Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz-Jampel syndrome (chondrodystrophic myotonia). Nat Genet. 2000 Dec;26(4):480-3
Spranger J, Hall BD, Häne B, Srivastava A, Stevenson RE. Spectrum of Schwartz-Jampel syndrome includes micromelic chondrodysplasia, kyphomelic dysplasia, and Burton disease. Am J Med Genet. 2000 Oct 2;94(4):287-95
Arikawa-Hirasawa E, Wilcox WR, Yamada Y. Dyssegmental dysplasia, Silverman-Handmaker type: unexpected role of perlecan in cartilage development. Am J Med Genet. 2001 Winter;106(4):254-7
Hopf M, Göhring W, Mann K, Timpl R. Mapping of binding sites for nidogens, fibulin-2, fibronectin and heparin to different IG modules of perlecan. J Mol Biol. 2001 Aug 17;311(3):529-41
Kvansakul M, Hopf M, Ries A, Timpl R, Hohenester E. Structural basis for the high-affinity interaction of nidogen-1 with immunoglobulin-like domain 3 of perlecan. EMBO J. 2001 Oct 1;20(19):5342-6
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Sabit H, Tsuneyama K, Shimonishi T, Harada K, Cheng J, Ida H, Saku T, Saito K, Nakanuma Y. Enhanced expression of basement-membrane-type heparan sulfate proteoglycan in tumor fibro-myxoid stroma of intrahepatic cholangiocarcinoma. Pathol Int. 2001 Apr;51(4):248-56
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HSPG2 (heparan sulfate proteoglycan 2) Farach-Carson MC, Grindel B
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Local order: The human IL21R gene maps on 16p11 between the IL4R and the GTF3C1 loci.
Note: The gene for interleukin 21 receptor is the partner of BCL6 in t(3;16)(q27;p11) translocation, which is recurrently observed in diffuse large B-cell lymphoma (Ueda, 2002).
DNA/RNA Description The IL21R gene is comprised of 9 exons (+2 alternative first exons), spanning 48.4kb on chromosome 16p11 (Parrish-Novak, 2000).
The human IL21R promoter region, contained within nucleotides -789 to +195 (relative to the start of exon 1a) induces the high levels of transcription in reporter assays (Ueda, 2002). A critical SP1 binding site is contained in the region from -80 to -20 and is essential for gene expression in human T cells (Wu, 2005). The DNA region (12MB) containing the IL21R gene contains multiple copies of large, duplicated segments (duplicons) originating in other regions of the genome (Loftus, 1999), which may predispose to additional duplications or deletions.
Transcription Three alternatively spliced transcript variants of 3248, 3361 and 3263 bp, each comprising 9 exons, have been described. They differ only for the alternative usage of a different first exon, which is contained within the 5' UTR region. Therefore these transcript variants encode for the same protein.
Diagram of IL21R gene organization and of the encoded transcripts. The IL21R gene is comprised of 11 exons and encodes for three alternatively spliced transcript variants that use a different first exon. As the first exon is contained within the 5' UTR region the three transcripts encode for the same protein.
IL21R (interleukin 21 receptor) Ferrini S, Fabbi M
The IL21R requires interaction with the common-gamma chain (γc) for mediating signal transduction upon IL21 binding. The tyrosine kinases JAK1 and JAK3 associate with the receptor complex and mediate receptor chain phosphorylation, recruitment and activation of downstream STAT1 and STAT3 molecules.
Description The IL21R gene encodes for a 538 aminoacid precursor protein with a 19 aminoacid signal peptide. The mature IL21R protein is a transmembrane glycoprotein with a molecular mass of approximately 75 kDA. IL21R is a type I cytokine receptor with an extracellular domain involved in cytokine binding, which contains one copy of the conserved WSXWS (Trp-Ser-X-Trp-Ser) motif, two fibronectin type-III domains of about 100 amino acids each, and conserved cysteine residues (Parrish-Novak, 2000). IL21R has a transmembrane domain followed by a large intracellular domain that contains the Box 1 and Box 2 elements shown to be important in signal transduction, and six tyrosine residues. The IL-21R also displays a consensus motif for STAT3 binding in its C-terminal tail. IL21R forms a heterodimeric receptor complex with the common gamma-chain (CD132) (Asao, 2001), which is also shared as subunit by the receptors for interleukin 2, interleukin 4, interleukin 7, interleukin 9, and interleukin 15.
Expression IL21R is expressed on normal B, T and NK lymphoid cells and also on monocyte/macrophages and dendritic cells. It is of note that also certain lymphoid neoplasias, such as multiple myeloma, Hodgkin's and non-Hodgkin's lymphomas, B-chronic lymphocytic leukemia and acute T cell leukemia express IL21R.
IL21R expression has been reported on other non-immune cell types such as intestinal epithelium in inflammatory bowel disease (Caruso, 2007a), gastric epithelium in Helicobacter pylori infection (Caruso 2007b) and rheumatoid synovium (Jungel, 2004).
Localisation IL21R protein is localized at the cell membrane.
Function The IL21R mediates the pleiotropic biological activities of IL21, the lastly identified member of the IL2 family (Parrish-Novak, 2000). IL21 co-stimulates mature T and B cell proliferation and differentiation and also potentiate NK cytolytic functions, inducing NK terminal differentiation (Kasaian, 2002). IL21 also promotes proliferation, cytotoxic function and IFN-gamma production by murine and human CD8+ effector T cells (Parrish-Novak, 2000; Strengell, 2003; Di Carlo 2004). IL21R signaling may mediate B cell proliferation and survival or B-cell apoptosis, in relationship to the activation status of the B cells (Ozaki, 2004; Metha, 2003; Jin, 2004). Mice deficient of IL21R (IL21R -/-) show defects in antibody production (in particular decreased IgG1 and increased IgE production in response to antigen stimulation) and reduced CTL responses, although their CD8+ T cell numbers are normal (Ozaki, 2002). The IL21/IL21R system is also a regulator of Th17 development and activity (Wei, 2007). The IL21R/common gamma chain complex, upon engagement of its specific ligand IL21, mediates signal transduction through the activation of downstream signaling molecules. These include the tyrosine kinases JAK1 and JAK3, which phosphorylate STAT1 and STAT3 (Zeng, 2007; de Totero, 2008). Differently from IL2 and IL15, which also use the common gamma chain and JAK3 for signaling and are strong inducers of STAT5 activation, IL21 is a weak inducer of STAT5 activation. IL21R signaling also leads to weak activation of both the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase pathways (PI3K) (Zeng, 2007).
Homology IL21R displays structural homologies with other members of the type I cytokine receptor family, such as the IL2Rbeta chain (29% identity, 46% similarity), IL9R, IL4R and IL7R. It has been initially described as an orphan cytokine receptor, structurally related to the IL2Rbeta (Parrish-Novak, 2000; Ozaki, 2000).
Mutations Note Not yet described. Genetic polymorphisms of IL21R have been described (Heckert, 2003). The IL21 variant bearing the (T-83C) genetic polymorphism has been associated with
IL21R (interleukin 21 receptor) Ferrini S, Fabbi M
increased IgE levels in females, suggesting a possible role of this IL21R polymorphism in allergy.
Implicated in Multiple myeloma (MM) Disease IL21R is expressed on MM cell lines and primary cells. IL21 induced proliferation and inhibited apoptosis of IL6-dependent human myeloma cell lines. Tumor necrosis factor (TNF) up-regulated the expression of IL21R and combinations of TNF and IL21 synergistically mediated myeloma cell proliferation. Four out of 9 purified primary myeloma cells showed increased DNA synthesis in response to IL21 (Brenne, 2002).
HTLV-I-infected cell lines and Acute T cell leukemia (ATL) Disease HTLV-I-infected cell lines and primary ATL cells expressed IL21R mRNA and surface protein. IL21 induced the proliferation of ATL cell lines and activated the phosphorylation of the STAT3 and STAT5. These findings suggest that the IL21/IL21R system may represent a target for the treatment of ATL (Ueda, 2005).
Hodgkin lymphoma (HL) Disease IL21R as well as IL21 are expressed by HL cells. IL21 activates STAT3 and STAT5 in HL cell lines. Expression of a constitutively active STAT5 molecule in normal human B cells immortalized them. These data suggest that the IL21/IL21R system may activate auto/para-crine loops involved in HL genesis via STAT5 activation (Sheeren, 2008). IL21 also protects HRS cells from CD95 death receptor-induced apoptosis and up-regulates the CC chemokine macrophage-inflammatory protein-3alpha (MIP-3alpha), which attracts regulatory T cells towards HL cells (Lamprecht, 2008).
B-Chronic Lymphocytic Leukemia (B-CLL) Disease B-CLL cells express IL21R at variable levels and stimuli such as CpG-ODN (Jahrsdorfer, 2006) or CD40L (de Totero, 2006) induce up-regulation of IL-21R expression. IL21 mediates apoptosis in B-CLL acting in synergy with these stimuli and may also cooperate with chemotherapy (fludarabine) or anti-CD20 therapeutic antibodies (Gowda, 2008). IL21 may limit the expansion of the CLL clone by inducing apoptosis and counteracting the mitogenic growth factors, such as IL15 (de Totero, 2008) and is being considered as a possible therapeutic agent in CLL (Gowda, 2008).
Follicular lymphoma (FL) Disease IL21R is expressed on FL cell lines and primary cells. In some FL cell lines IL21 induces apoptosis (Akamatsu, 2007).
Diffuse large B-cell lymphoma (DLBCL) Disease DLBCL is associated in about 28.6-35.5% with BCL6 translocation, which can involve either one of the immunoglobulin genes (IGs) but also other non-IG partners. IL21R gene represents one of such non-Ig fusion partners of BCL6 in the t(3;16) translocation (Ueda, 2002).
Cytogenetics FISH of lymphoma metaphase cells revealed fusion signals that contained both the BCL6 and IL21R sequences on the der(3)t(3;16) chromosome.
Hybrid/Mutated gene As a result of the t(3;16) translocation, the promoter region of IL21R was substituted for the regulatory sequences of BCL6. RT-PCR analyses revealed the presence of a chimeric mRNA consisting of two non-coding exons 1a/1b of IL21R and coding exons of BCL6 in the two lymphoma cells. BCL6 was moderately expressed at the mRNA and protein level under the control of IL21R promoter (Ueda, 2002).
Abnormal protein None.
Oncogenesis Unknown role.
Autoimmune diseases, allergy and neoplasia Note Several evidences in experimental murine models indicate that the IL21/IL21R system may be involved in immune-mediated disorders, such as autoimmune diabetes (Spolski, 2008b), arthritis (Jungel, 2004) and lupus (Herber, 2007). In view of its immune-enhancing activities IL21 has been regarded as a suitable molecule for cancer immunotherapy (reviewed in Di Carlo, 2007; Sploski, 2008a; Skak, 2008) and clinical phase I clinical trials in melanoma and renal carcinoma have shown acceptable toxicities and clinical activity (Thompson, 2008). In addition, the IL21/IL21R system may play a role in several hematological neoplasias that express the IL21R. The effects of IL21R signaling may however be strikingly different in different neoplastic conditions, as it may transduce mitogenic or survival signals or on the opposite trigger apoptotic cell death. Thus the IL21/IL21R system may represent a therapeutic target for inhibitory molecules in certain hematologic neoplasias, whereas in others IL21 may represent a possible therapeutic agent.
IL21R (interleukin 21 receptor) Ferrini S, Fabbi M
Inflammatory bowel disease (IBD) Disease IL21R is expressed at high levels on intestinal epithelial cells and stomal fibroblasts in IBD. IL21 induced macrophage inflammatory protein-3 alpha (MIP-3alpha), a T-cell chemoattractant in epithelial cells. Therefore IL21 has been involved in the cross-talk between epithelial and immune cells in the gut (Caruso 2007b).
Rheumatoid Arthritis (RA) Disease Both synovial macrophages and synovial fibroblasts expressed IL21R in synovial biopsy samples from RA patients. IL21R is associated with the activated phenotype of fibroblasts (Jungel, 2004).
Helicobacter pylori (HP) gastritis Disease Hp infection is associated with gastric inflammation. IL21R is expressed by primary gastric epithelial cells and cell lines, which respond to IL21 by increasing production of MMP-2 and MMP-9. Since IL21 is overexpressed in Hp-infected gastric mucosa it could contribute to increased epithelial gelatinase production (Caruso, 2007a).
Breakpoints Note Two t(3;16)(q27;p11) breakpoints on 16p11 are both localized within the intron 1 of IL-21R gene in two different DLBCL (Ueda, 2002).
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DNA/RNA Description A full-length mouse cDNA clone encoding KLF4 was initially isolated from a NIH3T3 cDNA library by reduced stringency screening with a DNA probe containing the zinc finger region of an immediate early gene product, Zif268 or Egr1. A distinct feature of the KLF4 gene is the highly GC-rich nature of the sequence near its 5'-end. Thus, the G+C content of the 1000 nt 5'-flanking region is 67% and that of the 5'-untranslated region is 63%. Moreover, the bulk of the GC residues are concentrated in the region between nt -600 and +300 of the gene where the G+C content is 82%. The gene has four exons, each containing a portion of the translated region.
Transcription The open-reading frame of the Klf4 gene encodes a polypeptide of 483 amino acids with a predicted
molecular weight of 53 kDa. The entire polypeptide sequence of Klf4 with the exception of the first amino acid is encoded by exons 2, 3 and 4.
Protein Description KLF4 encodes a polypeptide of 483 aa and similar to KLFs, contains three Kruppel-type zinc fingers in the very C-terminal end. The region immediately N terminal to the three zinc fingers is a 20-aa peptide containing a cluster of basic aa residues, which is essential for the nuclear localization of the protein.
Expression KLF4 is a nuclear protein whose cellular address depends on two nuclear localization signals. Expression of the KLF4 gene is developmentally regulated, with a higher level of expression occurring toward the later stage of fetal development. In adults, KLF4 is highly enriched in epithelial tissues, including the skin, lung, and intestine. In the intestinal tract, KLF4 is predominantly present in the terminally differentiated, postmitotic epithelial cells lining the villus border of the small intestine and the upper crypt region of the large intestine.
The structure of the murine KLF4 gene. The four exons of the murine GKLF gene are identified by Roman numerals. The translated region or open reading frame is depicted in black. The locations of restriction sites for several endonucleases are labeled: Nc, NcoI; N, NotI; K, KpnI; H, HindIII; Xh, XhoI; Sm, SmaI; Xb, XbaI; Bg, BglII; B, BamHI.
KLF4 (Kruppel-like factor 4 (gut)) Ghaleb AM, Yang VW
In cultured cells, the level of KLF4 mRNA is associated with the growth-arrested state in a manner similar to that observed in the intestinal epithelium. Expression of KLF4 can also be found in a select number of other organs including the lung, testis, skin and thymus, and in vascular endothelial cells.
Localisation KLF4 is a nuclear protein that contains two potent nuclear localization signals (NLSs), one within the three zinc fingers and the other in a cluster of basic amino acids immediately adjacent to the first zinc finger. These two NLSs define a subfamily of three closely related KLFs: KLF1, KLF2, and KLF4.
Function KLF4 binds to DNA sequence elements that are GC-rich. A consensus DNA binding sequence was empirically determined and is present in the promoters of many genes, including the CACCC element and the basic transcription element (BTE). KLF4 inhibits the promoter of the cytochrome P-450IA1 (CYP1A1) gene in a BTE-dependent manner. In cultured cells, the level of KLF4 mRNA is associated with the growth-arrested state in a manner similar to that observed in the intestinal epithelium.
Forced expression of KLF4 in cultured cells results in the inhibition of DNA synthesis. The induction of KLF4 is also correlated with an increase in the level of p21WAF1/CIP1, a critical checkpoint protein that inhibits cell cycle progression and is essential in mediating the cell cycle arrest at both the G1/S and G2/M boundaries. Importantly, KLF4 is essential in the induction of expression of the p21WAF1/CIP1 gene in response to DNA damage by binding to a specific cis-DNA element in the p21WAF1/CIP1 proximal promoter to activate p21WAF1/CIP1 expression. cDNA microarray analysis of the transcriptional profiles of KLF4 demonstrates that KLF4 inhibits the cell cycle by coordinately regulating expression of numerous cell cycle regulatory genes. KLF4 mediates the cell cycle checkpoint function of the tumor suppressor p53 suggesting that it may itself act as a tumor suppressor. Its mRNA are reduced in intestinal adenomas of ApcMin/+ mice and colonic adenomas of patients with familial adenomatous polyposis (FAP) when compared with surrounding normal tissues. Conversely, overexpression of KLF4 in the human colon cancer cell line RKO, which does not express endogenous KLF4, results in reduced tumorigenesis in vitro and in vivo. KLF4 plays a role in mediating the tumor-suppressive function of APC. KLF4 can down-regulate the level of beta-catenin and can bind directly to the transcriptional activation domain of beta-catenin to inhibit beta-catenin-mediated transcription. KLF4 haploinsufficiency in ApcMin/+ mice lead to significantly more intestinal adenomas than ApcMin/+ mice alone. In vivo, KLF4 is required for goblet cell differentiation in the intestine and eye conjuctiva. KLF4 has been shown to be down-regulated by Notch pathway and is important in maintaining the normal skin barrier. Induction of KLF4 significantly reduces the percentage of apoptotic cells following g-irradiation. Upregulation of KLF4 also inhibits expression of the gene encoding the pro-apoptotic protein Bax following DNA damage. Taken together, these studies place KLF4 in an interesting and important position between the Wnt and Notch signaling pathways, both of which are crucial for intestinal tumorigenesis. Additional studies are likely to further reveal the exact mechanism by which KLF4 mediates the crosstalk functions of these two key pathways in CRC.
Homology KLF4 belongs to the SP1 / KLF transcription factor family that is highly conserved among species (from Drosophila to human). Mouse KLF4 and is 90% identical to human KLF4. The carboxyl terminus of KLF4 contains three C2H2-zinc fingers that are most closely related to another member of the family, KLF2.
KLF4 (Kruppel-like factor 4 (gut)) Ghaleb AM, Yang VW
Mutations Note A number of colon cancer cell lines contain point mutations in the coding region of KLF4 that resulted in a diminished ability to activate the p21WAF1/Cip1 promoter. Also there is evidence for LOH of the KLF4 locus and of hypermethylation of the 5'-UTR in resected CRC specimens and colon cancer cell lines.
Implicated in Colorectal Cancer (CRC) Disease The relevance of KLF4 in the pathogenesis of human CRC is demonstrated by a significant reduction of KLF4 mRNA levels in colorectal adenoma and adenocarcinoma compared with matched normal colonic tissues. There is also evidence for LOH in a subset of CRC and in a panel of CRC cell lines. Moreover, the 5-untranslated region of the KLF4 gene is found to be hypermethylated in a subset of CRC. Lastly, several point mutations are identified in KLF4 that result in a diminished ability to activate the p21WAF1/CIP1 promoter in some of the CRC cell lines. These studies suggest that KLF4 is a tumor suppressor, at least in a fraction of patients with CRC. Recent studies demonstrating that KLF4 is involved in maintaining centrosome duplication and thus genomic stability further illustrate the mechanism by which KLF4 may be involved in tumor suppression.
Goblet cells hypoplasia Disease Mice homozygous for a null mutation in the Klf4 gene die shortly after birth, for unknown reasons. Immediately following birth, Klf4-/- mice have a 90% reduction in the number of goblet cells in their colon, show abnormal expression of the goblet cell-specific marker Muc2, and have abnormal goblet cell morphology.
Gastric cancer Disease Mutational analysis indicates that the KLF4 gene is subject to deletion, mutation and methylation silencing in a significant proportion of colon and gastric cancers. Conditional Klf4-knockout mouse specific for the gastric epithelium, loss of Klf4 results in increased proliferation and differentiation in the stomach, culminating in precancerous changes altered.
Breast cancer Disease KLF4 levels are elevated in up to 70% of mammary carcinomas.
Prognosis Nuclear localization of KLF4 is associated with an aggressive phenotype in early stage breast cancer.
Oncogenesis Oncogene.
Dysplastic oral squamous-cell carcinomas Disease KLF4 levels are elevated in oropharyngial dysplastic squamous-cell carcinomas.
Squamous cell carcinoma Disease Ectopic expression of KLF4 in basal keratinocytes of transgenic mice results in dysplastic lesions that resemble squamous cell carcinoma in situ.
References Schuh R, Aicher W, Gaul U, Côté S, Preiss A, Maier D, Seifert E, Nauber U, Schröder C, Kemler R. A conserved family of nuclear proteins containing structural elements of the finger protein encoded by Krüppel, a Drosophila segmentation gene. Cell. 1986 Dec 26;47(6):1025-32
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Garrett-Sinha LA, Eberspaecher H, Seldin MF, de Crombrugghe B. A gene for a novel zinc-finger protein
KLF4 (Kruppel-like factor 4 (gut)) Ghaleb AM, Yang VW
expressed in differentiated epithelial cells and transiently in certain mesenchymal cells. J Biol Chem. 1996 Dec 6;271(49):31384-90
Shields JM, Christy RJ, Yang VW. Identification and characterization of a gene encoding a gut-enriched Krüppel-like factor expressed during growth arrest. J Biol Chem. 1996 Aug 16;271(33):20009-17
Koritschoner NP, Bocco JL, Panzetta-Dutari GM, Dumur CI, Flury A, Patrito LC. A novel human zinc finger protein that interacts with the core promoter element of a TATA box-less gene. J Biol Chem. 1997 Apr 4;272(14):9573-80
Shields JM, Yang VW. Two potent nuclear localization signals in the gut-enriched Krüppel-like factor define a subfamily of closely related Krüppel proteins. J Biol Chem. 1997 Jul 18;272(29):18504-7
Ton-That H, Kaestner KH, Shields JM, Mahatanankoon CS, Yang VW. Expression of the gut-enriched Krüppel-like factor gene during development and intestinal tumorigenesis. FEBS Lett. 1997 Dec 15;419(2-3):239-43
Jenkins TD, Opitz OG, Okano J, Rustgi AK. Transactivation of the human keratin 4 and Epstein-Barr virus ED-L2 promoters by gut-enriched Krüppel-like factor. J Biol Chem. 1998 Apr 24;273(17):10747-54
Shields JM, Yang VW. Identification of the DNA sequence that interacts with the gut-enriched Krüppel-like factor. Nucleic Acids Res. 1998 Feb 1;26(3):796-802
Yet SF, McA'Nulty MM, Folta SC, Yen HW, Yoshizumi M, Hsieh CM, Layne MD, Chin MT, Wang H, Perrella MA, Jain MK, Lee ME. Human EZF, a Krüppel-like zinc finger protein, is expressed in vascular endothelial cells and contains transcriptional activation and repression domains. J Biol Chem. 1998 Jan 9;273(2):1026-31
Zhang W, Shields JM, Sogawa K, Fujii-Kuriyama Y, Yang VW. The gut-enriched Krüppel-like factor suppresses the activity of the CYP1A1 promoter in an Sp1-dependent fashion. J Biol Chem. 1998 Jul 10;273(28):17917-25
Mahatan CS, Kaestner KH, Geiman DE, Yang VW. Characterization of the structure and regulation of the murine gene encoding gut-enriched Krüppel-like factor (Krüppel-like factor 4). Nucleic Acids Res. 1999 Dec 1;27(23):4562-9
Panigada M, Porcellini S, Sutti F, Doneda L, Pozzoli O, Consalez GG, Guttinger M, Grassi F. GKLF in thymus epithelium as a developmentally regulated element of thymocyte-stroma cross-talk. Mech Dev. 1999 Mar;81(1-2):103-13
Segre JA, Bauer C, Fuchs E. Klf4 is a transcription factor required for establishing the barrier function of the skin. Nat Genet. 1999 Aug;22(4):356-60
Dang DT, Bachman KE, Mahatan CS, Dang LH, Giardiello FM, Yang VW. Decreased expression of the gut-enriched Krüppel-like factor gene in intestinal adenomas of multiple intestinal neoplasia mice and in colonic adenomas of familial adenomatous polyposis patients. FEBS Lett. 2000 Jul 7;476(3):203-7
Dang DT, Pevsner J, Yang VW. The biology of the mammalian Krüppel-like family of transcription factors. Int J Biochem Cell Biol. 2000 Nov-Dec;32(11-12):1103-21
Foster KW, Frost AR, McKie-Bell P, Lin CY, Engler JA, Grizzle WE, Ruppert JM. Increase of GKLF messenger RNA and protein expression during progression of breast cancer. Cancer Res. 2000 Nov 15;60(22):6488-95
Shie JL, Chen ZY, O'Brien MJ, Pestell RG, Lee ME, Tseng CC. Role of gut-enriched Krüppel-like factor in colonic cell growth
and differentiation. Am J Physiol Gastrointest Liver Physiol. 2000 Oct;279(4):G806-14
Zhang W, Geiman DE, Shields JM, Dang DT, Mahatan CS, Kaestner KH, Biggs JR, Kraft AS, Yang VW. The gut-enriched Kruppel-like factor (Kruppel-like factor 4) mediates the transactivating effect of p53 on the p21WAF1/Cip1 promoter. J Biol Chem. 2000 Jun 16;275(24):18391-8
Chen X, Johns DC, Geiman DE, Marban E, Dang DT, Hamlin G, Sun R, Yang VW. Krüppel-like factor 4 (gut-enriched Krüppel-like factor) inhibits cell proliferation by blocking G1/S progression of the cell cycle. J Biol Chem. 2001 Aug 10;276(32):30423-8
Katz JP, Perreault N, Goldstein BG, Lee CS, Labosky PA, Yang VW, Kaestner KH. The zinc-finger transcription factor Klf4 is required for terminal differentiation of goblet cells in the colon. Development. 2002 Jun;129(11):2619-28
Chen X, Whitney EM, Gao SY, Yang VW. Transcriptional profiling of Krüppel-like factor 4 reveals a function in cell cycle regulation and epithelial differentiation. J Mol Biol. 2003 Feb 21;326(3):665-77
Dang DT, Chen X, Feng J, Torbenson M, Dang LH, Yang VW. Overexpression of Krüppel-like factor 4 in the human colon cancer cell line RKO leads to reduced tumorigenecity. Oncogene. 2003 May 29;22(22):3424-30
Yoon HS, Chen X, Yang VW. Kruppel-like factor 4 mediates p53-dependent G1/S cell cycle arrest in response to DNA damage. J Biol Chem. 2003 Jan 24;278(4):2101-5
Pandya AY, Talley LI, Frost AR, Fitzgerald TJ, Trivedi V, Chakravarthy M, Chhieng DC, Grizzle WE, Engler JA, Krontiras H, Bland KI, LoBuglio AF, Lobo-Ruppert SM, Ruppert JM. Nuclear localization of KLF4 is associated with an aggressive phenotype in early-stage breast cancer. Clin Cancer Res. 2004 Apr 15;10(8):2709-19
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Foster KW, Liu Z, Nail CD, Li X, Fitzgerald TJ, Bailey SK, Frost AR, Louro ID, Townes TM, Paterson AJ, Kudlow JE, Lobo-Ruppert SM, Ruppert JM. Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia. Oncogene. 2005 Feb 24;24(9):1491-500
Ghaleb AM, Nandan MO, Chanchevalap S, Dalton WB, Hisamuddin IM, Yang VW. Krüppel-like factors 4 and 5: the yin and yang regulators of cellular proliferation. Cell Res. 2005 Feb;15(2):92-6
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van Es JH, van Gijn ME, Riccio O, van den Born M, Vooijs M, Begthel H, Cozijnsen M, Robine S, Winton DJ, Radtke F, Clevers H. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature. 2005 Jun 16;435(7044):959-63
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KLF4 (Kruppel-like factor 4 (gut)) Ghaleb AM, Yang VW
Yoon HS, Ghaleb AM, Nandan MO, Hisamuddin IM, Dalton WB, Yang VW. Krüppel-like factor 4 prevents centrosome amplification following gamma-irradiation-induced DNA damage. Oncogene. 2005 Jun 9;24(25):4017-25
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DNA/RNA Note LOXL3 is part of the lysyl oxidase (LOX) family, the members of which are secreted extracellular matrix enzymes. LOXL3 contains a C-terminal region that is conserved in all five isoforms of this copper-dependent amine oxidase family. The domains included within this region are a copper-binding site, lysyl and tyrosine residues that form the lysyltyrosine-quinone cofactor (LTQ) and a cytokine receptor-like domain. The N-terminal region of the full-length LOXL3 contains four SRCR (scavenger receptor cysteine-rich) domains that have high levels of homology with the SRCR domains within LOXL2 and LOXL4, but not with the N-terminal part of LOX or LOXL that do not contain SRCR domains.
Description The human LOXL3 gene has 14 exons that span more than 21 kb of genomic sequence located on chromosome 2p13.3. The LOXL3 gene has been described to have a 2262 bases (Jourdan-LeSaux et al., 2001) long open reading frame (reported as 2226 bp by Maki et al., 2001) and a 3' UTR of 787 bases.
Transcription The human LOXL3 cDNA is 3121 bases long. The 3' UTR has three consensus polyadenylation signal sequences. In the 3' UTR there are three AU-rich sequence elements that are usually found within the 3' trailer region of unstable mRNAs.
Alternative splicing was detected in ESTs that appear to represent tissue-specific splice forms of the LOXL3 mRNA. The alternatively spliced LOXL3 mRNA lacks exons 1, 2, 3, and 5 with an exon-intron structure distinct from the full-length LOXL3, and additionally, contains 80 bps in its 5' UTR and 561 bps in its 3'UTR. The protein deduced from this alternative mRNA retains the structural C-terminal elements of a LOX family protein and the fourth SRCR domain at its N-terminus and is predicted to encode a polypeptide of 392 amino acids with a predicted molecular mass of 44 kDa. In Northern blot analyses of multiple human tissue samples, LOXL3 mRNA was detected at 3.1 kb using PCR-generated (Maki et al., 2001) and at 3.3 kb using EST-derived probes (Jourdan-LeSaux et al., 2001).
Protein Note Western blot analysis of HT-1080 cells detected the recombinant cellular and secreted form of the LOXL3 protein as a band of 97 kDa, slightly larger than the predicted overall mass of 83.6 kDa for the recombinant LOXL3, a size difference probably due to cell-type dependent glycosylation.
Description The predicted LOXL3 protein is 753 (also reported as 754, Jourdan-LeSaux et al., 2001) amino acids long with a 25 amino acid long predicted signal peptide and with a calculated molecular mass of approximately 80.3 kDa. The C-terminal region, (aa. 529-729, Maki et al., 2001) contains the conserved lysyl oxidase domain, including the putative copper binding sequence (aa. 601-611, Maki et al., 2001; 601-612, Jourdan-LeSaux et al., 2001), the lysyl (aa. 634, Maki et al., 2001; 639, Jourdan-LeSaux et al., 2001) and tyrosyl (aa. 689, Maki
LOXL3 (lysyl oxidase-like 3) Szauter KM, Csiszar K
et al., 2001; 670, Jourdan-LeSaux et al., 2001) residues that form the lysyltyrosylquinone cofactor, and the cytokine receptor-like motif (aa. 666-727, Jourdan-LeSaux et al., 2001). In the N-terminal region the four scavenger receptor cysteine-rich domains are located at aa. 44-144, 186-281, 307-407, and 417-526 (Jourdan-LeSaux et al., 2001) and a putative nuclear localization signal is at aa. 293-311. The processed LOXL3 polypeptide contains three putative O-glycosylation sites and five potential N-glycosylation sites. There is a putative BMP-1 processing site between amino acid residues 446-448 (Jourdan-LeSaux et al., 2001).
Expression Tissues: Human LOXL3 mRNA is expressed in leucocytes, in the adult human aorta, neurons, spinal cord, brain, heart, uterus, ovary, testis, prostate, small intestine and spleen. Low mRNA expression was found in the kidney, skeletal muscle and placenta. Expression of the human LOXL3 splice variant mRNA was detected in the kidney, pancreas, spleen and thymus, indicating distinct tissue specificity. Human LOXL3 protein was detected in the testis, and lung at 44kDa, corresponding to the short spice variant. In the placenta, and colon both the splice product 44 kDa and the full-length 67 kDa LOXL3 were reported. In mice, LOXL3 protein expression was reported in the tunica media of the adult heart, in aortic smooth muscle cells, and in the cytoplasm of the myocardium. Nuclear localization was detected in the kidney and liver. Cytoplasmic LOXL3 was present in hepatocytes. In the kidney, LOXL3 protein is expressed in the distal and proximal convoluted tubes and the collecting tubes. Strong LOXL3 protein expression was noted in embryonic murine chondrocytes and in skin, epidermis and dermis. Cell lines: Human LOXL3 mRNA was expressed in the highly invasive breast cancer cell line Hs578T, highly invasive/metastatic human MDA435 cells derived from pleural effusion from a female patient with an infiltrating ductal carcinoma, and human A375P melanoma cell lines. No LOXL3 mRNA expression was detected in MCF7, T47D and MDA MB-231 breast cancer lines. Murine LOXL3 mRNA was expressed in the C2C12 myoblast cell line, and the highly metastatic HaCa4 squamous cell carcinoma and CarB spindle cell carcinoma cell lines.
Localisation Nuclear localization was noted in the mouse kidney and liver. In transiently transfected MDKC cells LOXL3 showed perinuclear localization. Cytoplasmic expression was found in the murine myocardium and in hepatocytes. Recombinant LOXL3 protein in human HT-1080 fibrosarcoma cell lines localized both intra- and extracellularly.
Function LOXL3 likely functions as an amine oxidase, as BetaAPN (Beta-aminopropionitrile) inhibitable enzymatic activity was noted for a recombinant human LOXL3 generated in an E. coli expression system. The recombinant full length LOXL3 showed high catalytic activity towards collagen type I, IV, VIII, X and lower activity against collagen type VI substrates. The splice variant LOXL3 showed highest activity against type IV collagen as a substrate.
Homology LOXL3 has high level of homology with the C-terminal domains of LOX, LOXL1, LOXL2 and LOXL4 and homology with the four N-terminal SRCR domains within LOXL2 and LOXL4.
Implicated in Breast cancer Note LOXL3 mRNA was expressed in Hs578T highly invasive breast cancer cells, but not in poorly invasive and non-metastatic breast cancer cells MCF7 and T47D.
Disease Breast cancer invasion.
Epithelial-mesenchymal transition (EMT) - tumor progression Note LOXL3 interacts and collaborates with SNAI1 (SNAIL, 20q13.2) to downregulate E-cadherin expression. Overexpression of LOXL3 in MDCK epithelial cells induces an EMT process.
References Huang Y, Dai J, Tang R, Zhao W, Zhou Z, Wang W, Ying K, Xie Y, Mao Y. Cloning and characterization of a human lysyl oxidase-like 3 gene (hLOXL3). Matrix Biol. 2001 Apr;20(2):153-7
Jourdan-Le Saux C, Tomsche A, Ujfalusi A, Jia L, Csiszar K. Central nervous system, uterus, heart, and leukocyte expression of the LOXL3 gene, encoding a novel lysyl oxidase-like protein. Genomics. 2001 Jun 1;74(2):211-8
Mäki JM, Kivirikko KI. Cloning and characterization of a fourth human lysyl oxidase isoenzyme. Biochem J. 2001 Apr 15;355(Pt 2):381-7
Kirschmann DA, Seftor EA, Fong SF, Nieva DR, Sullivan CM, Edwards EM, Sommer P, Csiszar K, Hendrix MJ. A molecular role for lysyl oxidase in breast cancer invasion. Cancer Res. 2002 Aug 1;62(15):4478-83
Molnar J, Fong KS, He QP, Hayashi K, Kim Y, Fong SF, Fogelgren B, Szauter KM, Mink M, Csiszar K. Structural and functional diversity of lysyl oxidase and the LOX-like proteins. Biochim Biophys Acta. 2003 Apr 11;1647(1-2):220-4
LOXL3 (lysyl oxidase-like 3) Szauter KM, Csiszar K
Peinado H, Del Carmen Iglesias-de la Cruz M, Olmeda D, Csiszar K, Fong KS, Vega S, Nieto MA, Cano A, Portillo F. A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression. EMBO J. 2005 Oct 5;24(19):3446-58
Lee JE, Kim Y. A tissue-specific variant of the human lysyl oxidase-like protein 3 (LOXL3) functions as an amine oxidase with substrate specificity. J Biol Chem. 2006 Dec 8;281(49):37282-90
Kaku M, Mochida Y, Atsawasuwan P, Parisuthiman D, Yamauchi M. Post-translational modifications of collagen upon BMP-induced osteoblast differentiation. Biochem Biophys Res Commun. 2007 Aug 3;359(3):463-8
This article should be referenced as such:
Szauter KM, Csiszar K. LOXL3 (lysyl oxidase-like 3). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9):644-646.
DNA/RNA Note The gene for human C4.4A is located on chromosome 19q13, only 180 kb apart from the
urokinase-type plasminogen activator receptor (uPAR) gene, in a cluster encompassing all presently known glycosylphosphatidylinositol (GPI)-anchored, multi-domain proteins of the Ly6/uPAR/alpha-neurotoxin (LU) domain family.
Description 4870 bp; 5 exons (Figure 1).
Transcription Transcription of the C4.4A gene is regulated by the transcription factor C/EBPbeta (Fries et al., 2007).
Figure 1: Position of the C4.4A gene in the uPAR-like gene cluster on chromosome 19q13. The intron-exon organisation of the C4.4A gene reveals that separate exons encode the two LU domains of C4.4A, each of them with an internal phase-1 intron at loop 2, which in the three-finger LU fold is surface-exposed.
LYPD3 (LY6/PLAUR domain containing 3) Jacobsen B, Ploug M
Protein Note C4.4A is a GPI-anchored, multi-domain member of the Ly6/uPAR/alpha-neurotoxin (LU) protein domain family. C4.4A was identified by two independent groups seeking to identify cancer-related genes, the first observing that C4.4A was expressed in a metastasizing rat pancreatic adenocarcinoma cell line, but not on its non-metastasizing counterpart (Matzku et al., 1989), and the second showing the upregulation of C4.4A in an in vitro model system for wound healing in the urothelium, mimicking the progression of urothelial cancer (Smith et al., 2001). These findings suggested a putative role of C4.4A in cancer invasion and metastasis.
Description C4.4A consists of 346 amino acid residues, including a 30 residues signal peptide at the N-
terminal and a C-terminal signal sequence for GPI anchorage (38 residues) that are cleaved post-translationally, yielding a mature protein of 278 residues, anchored to the cell membrane via GPI (Figure 2A). It contains two LU domains (domains I and II), each of about 90 amino acids, and a serine-, threonine-, proline-rich (STP-rich) region. LU domains adopt a "three-fingered" folding topology, that is characterized by 4 consensus disulfide bonds and an invariant C-terminal asparagine (Figure 2B). Intriguingly, domain I of C4.4A lacks one consensus cysteine bond, which is crucial to the proper folding of the single domain LU proteins. The STP-rich region is highly O-glycosylated, with 17 potential O-glycosylation sites. None of the 6 potential N-glycosylation sites of C4.4A are, however, located in this region. Differential degrees of glycosylation can probably explain the large variation in molecular weight observed in C4.4A from different sources (Hansen et al., 2004), deviating from the theoretical value of 36 kDa.
Figure 2: Protein structure of C4.4A. A - Structural representation of the two LU domains and the STP-rich region of C4.4A (modified from Hansen et al., 2004). Insert: Ribbon diagram of the three-finger fold of a single LU domain (made in PyMOL™(DeLano Scientific), using PDB coordinates 1NEA). B - Disulfide connectivity in C4.4A, with LU consensus cysteine bonds highlighted in yellow.
LYPD3 (LY6/PLAUR domain containing 3) Jacobsen B, Ploug M
Expression C4.4A is expressed in the suprabasal cells of squamous epithelia found in e.g. esophagus and skin, the basal layer being devoid of C4.4A (Figure 3A), and in the amnion membrane in human term placenta (Figure 3C) (Hansen et al., 2004). In mouse skin wound healing, which is a tissue remodelling process often used as a surrogate model for cancer invasion, C4.4A is upregulated by the migrating keratinocytes. C4.4A expression is also increased in phorbolester-induced hyperplasia of murine skin (Hansen et al., 2004), in the progression to melanoma (Seiter et al., 2001) and in urothelial transitional cell carcinomas (Smith et al., 2001). The preferential expression of C4.4A in normal epithelia of the squamous type is paralleled in cancer, where it is expressed in the tumour component of
primarily squamous cell carcinomas (SCC) and only to a lesser extent in adenocarcinomas (AC) (Wang et al., 2006), as demonstrated in non-small cell lung cancer (NSCLC) (Figure 3D) (Hansen et al., 2007). In esophageal squamous cell carcinomas (ESCC), C4.4A expression as present in the normal mucosa is lost upon transition to dysplasia and carcinoma in situ, but reappears at the invasive front of the tumour and in lymph node metastases (Figure 3B) (Hansen et al., 2008).
Localisation C4.4A is tethered to the cell membrane via a GPI-anchor, but can under certain conditions also be found intracellularly. A soluble fragment of C4.4A, termed C4.4A', resulting from cleavage in the protease-sensitive region between domain II and the STP-rich region, releasing the two N-terminal LU
Figure 3: Expression of C4.4A in normal and malignant human tissue. Staining of human tissue sections with a polyclonal rabbit anti-C4.4A antibody produced at the Finsen Laboratory (Copenhagen, Denmark). C4.4A-negative basal cells are indicated by an arrow in panels A and B. (A and B, reproduced from Hansen et al., 2008; C and D, from Jacobsen, unpublished).
LYPD3 (LY6/PLAUR domain containing 3) Jacobsen B, Ploug M
domains, has been described in esophageal tissue (Hansen et al., 2008).
Function Structural homology of C4.4A to the urokinase receptor, uPAR, is not reflected at the functional level, the function of C4.4A still being unknown. Circumstancial evidence, nevertheless, points to a role of C4.4A in the modulation of cell/cell and/or cell/matrix interactions: 1) The carbohydrate-binding protein galectin-3, which has been reported to be involved in cell/cell interactions, cell adhesion, migration, invasion and metastasis, has been identified as a ligand for C4.4A (Paret et al., 2005). 2) C4.4A and the cell adhesion molecule E-cadherin are co-expressed in the normal esophageal mucosa, and both are down-regulated in the progression to dysplasia (Hansen et al., 2008). 3) C4.4A-positive and not C4.4A-negative tumour cells are capable of penetrating a matrigel, and this process can be inhibited by a monoclonal anti-C4.4A antibody (Rosel et al., 1998). 4) Encapsulation of lung metastases in rats, arising after an intrafootpad injection with pancreatic tumour cells, disappears, when these tumour cells are transfected with C4.4A (Rosel et al., 1998). 5) C4.4A has recently been reported to be a novel substrate for the extracellular matrix-degrading metalloproteases ADAM10 and ADAM17 (A Disintegrin And Metalloprotease domain), which have been implicated in cell migration and proliferation, with a bearing on tumour invasion and metastasis (Esselens et al., 2008).
Homology C4.4A shows homology to uPAR and other multi-domain proteins of the Ly6/uPAR/alpha-neurotoxin protein domain family (PRV-1/CD177, TEX101, PRO4356, GPQH2552).
Implicated in Non-small cell lung cancer (NSCLC) Disease In an immunohistochemical study encompassing 104 patients with NSCLC, high levels of C4.4A were found in 77% of SCC and in 24% of AC (Hansen et al., 2007). Preliminary data on the expression of C4.4A in premalignant lesions of NSCLC indicate that C4.4A is present already at very early stages of lung cancer progression.
Prognosis A high level of C4.4A in NSCLC tissue correlates to a poorer survival of the patients (Figure 4). In the above-mentioned study, it was shown that this correlation primarily could be ascribed to a dramatic effect on the patients with AC and C4.4A levels above the median, all dying within 2 years (Hansen et al., 2007).
Figure 4: Impact of C4.4A on the prognosis of NSCLC patients. Kaplan-Meier survival curves for 104 patients with NSCLC (A) and the histological subgroup with adenocarcinomas (B), stratified by expression levels of C4.4A (modified from Hansen et al., 2007, with permission).
Esophageal squamous cell carcinoma (ESCC) Note C4.4A is absent in dysplastic esophageal epithelium as well as in early invasive ESCC, but shows a pronounced expression at the invasive front of the tumour deeper in the esophageal wall and in lymph node metastases, making C4.4A a possible new histological marker of invasion and metastasis in human ESCC (Hansen et al., 2008).
References Matzku S, Wenzel A, Liu S, Zöller M. Antigenic differences between metastatic and nonmetastatic BSp73 rat tumor variants characterized by monoclonal antibodies. Cancer Res. 1989 Mar 1;49(5):1294-9
Claas C, Herrmann K, Matzku S, Möller P, Zöller M. Developmentally regulated expression of metastasis-associated antigens in the rat. Cell Growth Differ. 1996 May;7(5):663-78
Rösel M, Claas C, Seiter S, Herlevsen M, Zöller M. Cloning and functional characterization of a new phosphatidyl-inositol anchored molecule of a metastasizing rat pancreatic tumor. Oncogene. 1998 Oct 15;17(15):1989-2002
LYPD3 (LY6/PLAUR domain containing 3) Jacobsen B, Ploug M
Seiter S, Stassar M, Rappl G, Reinhold U, Tilgen W, Zöller M. Upregulation of C4.4A expression during progression of melanoma. J Invest Dermatol. 2001 Feb;116(2):344-7
Smith BA, Kennedy WJ, Harnden P, Selby PJ, Trejdosiewicz LK, Southgate J. Identification of genes involved in human urothelial cell-matrix interactions: implications for the progression pathways of malignant urothelium. Cancer Res. 2001 Feb 15;61(4):1678-85
Würfel J, Seiter S, Stassar M, Claas A, Kläs R, Rösel M, Marhaba R, Savelyeva L, Schwab M, Matzku S, Zöller M. Cloning of the human homologue of the metastasis-associated rat C4.4A. Gene. 2001 Jan 10;262(1-2):35-41
Hansen LV, Gårdsvoll H, Nielsen BS, Lund LR, Danø K, Jensen ON, Ploug M. Structural analysis and tissue localization of human C4.4A: a protein homologue of the urokinase receptor. Biochem J. 2004 Jun 15;380(Pt 3):845-57
Paret C, Bourouba M, Beer A, Miyazaki K, Schnölzer M, Fiedler S, Zöller M. Ly6 family member C4.4A binds laminins 1 and 5, associates with galectin-3 and supports cell migration. Int J Cancer. 2005 Jul 10;115(5):724-33
Wang W, Ding YQ, Li ZG, Han HX, Yang L. [Expression and diagnostic application of C4.4A protein in squamous cell carcinoma and adenocarcinoma]. Zhonghua Bing Li Xue Za Zhi. 2006 May;35(5):277-80
Fries F, Nazarenko I, Hess J, Claas A, Angel P, Zöller M. CEBPbeta, JunD and c-Jun contribute to the transcriptional activation of the metastasis-associated C4.4A gene. Int J Cancer. 2007 May 15;120(10):2135-47
Hansen LV, Skov BG, Ploug M, Pappot H. Tumour cell expression of C4.4A, a structural homologue of the urokinase receptor, correlates with poor prognosis in non-small cell lung cancer. Lung Cancer. 2007 Nov;58(2):260-6
Esselens CW, Malapeira J, Colome N, Moss M, Canals F, Arribas J.. Metastasis-associated C4.4A, a GPI-anchored protein cleaved by ADAM10 and ADAM17. Biol Chem. 2008 Aug;389(8):1075-84.
Hansen LV, Laerum OD, Illemann M, Nielsen BS, Ploug M. Altered expression of the urokinase receptor homologue, C4.4A, in invasive areas of human esophageal squamous cell carcinoma. Int J Cancer. 2008 Feb 15;122(4):734-41
Jacobsen B, Ploug M. The urokinase receptor and its structural homologue C4.4A in human cancer: expression, prognosis and pharmacological inhibition. Curr Med Chem. 2008;15(25):2559-73
Identity Other names: B-MYB, B-Myb, BMYB, MGC15600, OTTHUMP00000031719
HGNC (Hugo): MYBL2
Location: 20q13.1
DNA/RNA Description 49,415 bases DNA with 14 exons.
Transcription 2,731 bases mRNA.
Protein Description 704 amino acids, 93kDa protein. R1, R2, R3 - three repeats 50 amino acids long, R2 and R3 contain HTH (helix-turn-helix) motives with unconventional turns required for DNA-binding activity, R1 serves as a DNA/protein complex stabilizer; TA contains acidic amino acids and is responsible for transcriptional activation; RD is responsible for repression of transactivation function of B-MYB.
red boxes: untranslated regions; green boxes: coding regions.
MYBL2 (v-myb myeloblastosis viral oncogene homolog (avian)-like 2) Chayka O, Sala A
R1, R2 and R3 form DNA-binding domain, TA - transactivation domain, CR - conserved region (the area of homology with c-Myb), RD -
regulatory domain.
Expression Widely expressed, expression is very high in proliferative cells, embryonic cells, haematopoietic progenitor cells.
Localisation Nucleus.
Function Transcription factor required for cell proliferation, cell cycle progression, chromosomal stability and differentiation. B-MYB knockout mice die at E4.5-E6.5 due to early developmental arrest.
Homology B-MYB is a member of MYB transcription factors family, which includes C-MYB and A-MYB, with high homology within TA and RD regions. DNA-binding domain is almost identical with that of A-MYB and C-MYB and conserved between mouse, human, chicken and drosophila.
Implicated in Neuroblastoma Prognosis Overexpression is thought to be associated with a poor outcome of the disease.
Oncogenesis Was reported to be necessary for survival and differentiation of neuroblastoma cells.
Hepatocellular carcinoma (HCC) Oncogenesis B-MYB is reported to be a probable target of E2F1 transcription factor, which is dramatically overexpressed in HCC. There is a clear correlation between expression level of these two proteins. B-MYB overexpression in HCC causes the deregulation of apoptosis and cell cycle.
Various cancer Disease Amplification of B-MYB was described in breast carcinomas, liver carcinomas, ovarian carcinomas and in cutaneous T lymphoma. B-MYB expression was shown also to be increased in prostate and testicular malignancies. Moreover, B-MYB expression is notably increased in metastatic compared to localised prostate tumours.
The presence of B-MYB polymorphisms rs2070235 and rs11556379 is associated with a significant reduction of cancer risk.
Oncogenesis B-MYB overexpression may result in promotion of cancer cells survival and proliferation. Polimorphisms can induce changes in protein conformation and therefore may in part deactivate B-MYB functions.
References Raschellà G, Negroni A, Sala A, Pucci S, Romeo A, Calabretta B. Requirement of b-myb function for survival and differentiative potential of human neuroblastoma cells. J Biol Chem. 1995 Apr 14;270(15):8540-5
Noben-Trauth K, Copeland NG, Gilbert DJ, Jenkins NA, Sonoda G, Testa JR, Klempnauer KH. Mybl2 (Bmyb) maps to mouse chromosome 2 and human chromosome 20q 13.1. Genomics. 1996 Aug 1;35(3):610-2
Oh IH, Reddy EP. The myb gene family in cell growth, differentiation and apoptosis. Oncogene. 1999 May 13;18(19):3017-33
Raschellà G, Cesi V, Amendola R, Negroni A, Tanno B, Altavista P, Tonini GP, De Bernardi B, Calabretta B. Expression of B-myb in neuroblastoma tumors is a poor prognostic factor independent from MYCN amplification. Cancer Res. 1999 Jul 15;59(14):3365-8
Sala A, Watson R. B-Myb protein in cellular proliferation, transcription control, and cancer: latest developments. J Cell Physiol. 1999 Jun;179(3):245-50
Tanaka Y, Patestos NP, Maekawa T, Ishii S. B-myb is required for inner cell mass formation at an early stage of development. J Biol Chem. 1999 Oct 1;274(40):28067-70
Schwab R, Caccamo A, Bettuzzi S, Anderson J, Sala A. B-MYB is hypophosphorylated and resistant to degradation in neuroblastoma: implications for cell survival. Blood Cells Mol Dis. 2007 Nov-Dec;39(3):263-71
Nakajima T, Yasui K, Zen K, Inagaki Y, Fujii H, Minami M, Tanaka S, Taniwaki M, Itoh Y, Arii S, Inazawa J, Okanoue T. Activation of B-Myb by E2F1 in hepatocellular carcinoma. Hepatol Res. 2008 Sep;38(9):886-95
Schwab R, Bussolari R, Corvetta D, Chayka O, Santilli G, Kwok JM, Ferrari-Amorotti G, Tonini GP, Iacoviello L, Bertorelle R, Menin C, Hubank M, Calabretta B, Sala A. Isolation and functional assessment of common, polymorphic variants of the B-MYB proto-oncogene associated with a reduced cancer risk. Oncogene. 2008 May 1;27(20):2929-33
This article should be referenced as such:
Chayka O, Sala A. MYBL2 (v-myb myeloblastosis viral oncogene homolog (avian)-like 2). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9):652-653.
Identity Other names: ARA70, DKFZp762E1112, ELE1, PTC3, RFG
HGNC (Hugo): NCOA4
Location: 10q11.23
DNA/RNA Description 10 exons, 3431bp.
Transcription Isoforms due to alternative splicing.
Protein Description Two isoforms: - Isoform alpha (614 aa, mass around 70kD) - Isoform beta: missing of aa 239-565 (mass around 32kD)
Expression NCOA4 is widely expressed in several tissues, including testis, adrenal and thyroid glands, thymus, prostate. A truncated NCOA4 corresponding to the beta isoform is fused to RET exon 12 and is aberrantly expressed in papillary thyroid carcinoma as a consequence of intrachromosomal rearrangements at 10q11.2 (RET/NCOA4).
Function NCOA4 is involved in the androgen receptor signaling pathway and in the development of the male gonade. It is a ligand-dependent associated
protein for the androgen receptor (AR), that functions as coactivator to enhance AR transcriptional activity (7-10 fold in human prostate cancer cells) and protein stability. NCOA4 also enhances the agonist activity of anti-androgens in human prostate cancer cells (3-30 fold in the prostate cancer cell line DU145), with relevant implications for hormonal treatment of prostate cancer. Albeit to a lesser degree (up to 2-fold), NCO4 also enhances transcription activity of other steroid receptors, such as glucocorticoid receptor (GR), progesterone receptor (PR) and oestrogen receptor (ER). In addition to the interaction with steroid hormone receptors, NCOA4 functions as coactivator of peroxisome proliferator-activated receptor gamma (PPARG). PPARG is a peroxisome proliferator-activated receptor and as such belongs to the nuclear hormone receptor superfamily. PPARG is highly expressed in adipose tissue (were it is involved in adipogenesis and in the regulation of adipocyte-specific genes), as well as in other human tissues. Interestingly, PPARG is rearranged with PAX8 in a subset of follicular thyroid tumors.
Ligand-specific interaction between AR (Androgen receptor), NCOA4, and the androgen receptor ligand DHT (dihydrotestosterone).
Unlike the AR-NCOA4 interaction, which requires the presence of androgen, the PPARG-NCOA4 interaction
NCOA4 (Nuclear Receptor Coactivator 4) de Biase D, et al.
can occur in the absence of exogenous ligand. However, the presence of the ligand enhances PPARG-NCOA4 transactivation and NCOA4 is thus regarded as a ligand-enhanced coactivator of PPARG.
Mutations Germinal LINE S94L; F154L; C350R; P474R; L561P.
Somatic NCOA4 breakpoint for rearrangement to form RET/NCOA4 oncogene at cDNA bp791, corresponding to aa 238-239.
Implicated in inv(10)(q11q11) with RET/NCOA4 rearrangement in thyroid cancer Disease Papillary thyroid carcinoma. RET/NCOA4 may occur in non radiation-associated carcinomas but it is particularly common in radiation-associated tumors like those linked to the Chernobyl nuclear accident (1986).
Prognosis RET/NCOA4 may be associated with aggressive behaviour. Among post-Chernobyl papillary carcinomas, RET/NCOA4 has been associated with tumors that were of shorter latency after radiation exposure, of larger size, with extrathyroidal extension, and that were classified as solid variant papillary carcinomas.
Cytogenetics Simple karyotypes with balanced chromosomal
inversions due to structural rearrangement of NCOA4 and RET gene on chromosome 10 [inv(10)(q11.2-q21)], resulting in RET/NCOA4.
Hybrid/Mutated gene RET/NCOA4.
Abnormal protein NCOA4/RET (RP3).
Oncogenesis RET/PTC oncogenes are generated by chromosomal rearrangements resulting in the fusion of the RET tyrosine-kinase (RET-TK) domain to the 5'-terminal region of heterologous genes (e.g. H4, RIa, RFG5, hTIF1, RFG7, ELKS). All are balanced inversions or translocations which involve the 3.0 kb intron 11 of RET. RET-fused genes are widely expressed in human tissues, including thyroid follicular cells, and have putative dimerization domains. As the chimeric forms of RET-TK are translated into fusion proteins, these domains of the translocated amino terminal regions allow dimerization and thus ligand independent activation of RET-TK, which is considered essential for the transformation of thyroid cells. To date, at least 16 chimeric mRNAs involving 10 different genes have been reported, of which RET/PTC1 (consisting in the fusion of RET with H4) and RET/NCOA4 (consisting in the fusion of RET with NCOA4) are by far the most common. ANIMAL MODELS RET/NCOA4 transgenic mice have been generated by Powell and coworkers using a construct with the RET/NCOA4 fusion gene downstream and under the control of the bovine thyroglobulin gene regulatory region; they express RET/NCOA4 selectively in the thyroid gland and develop thyroid hyperplasia and solid tumor variants of papillary carcinomas.
Diagram of RET/NCOA4 oncogene. The red arrow indicates the breakpoint region.
NCOA4 (Nuclear Receptor Coactivator 4) de Biase D, et al.
References Santoro M, Dathan NA, Berlingieri MT, Bongarzone I, Paulin C, Grieco M, Pierotti MA, Vecchio G, Fusco A. Molecular characterization of RET/PTC3; a novel rearranged version of the RETproto-oncogene in a human thyroid papillary carcinoma. Oncogene. 1994 Feb;9(2):509-16
Yeh S, Chang C. Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells. Proc Natl Acad Sci U S A. 1996 May 28;93(11):5517-21
Miyamoto H, Yeh S, Wilding G, Chang C. Promotion of agonist activity of antiandrogens by the androgen receptor coactivator, ARA70, in human prostate cancer DU145 cells. Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7379-84
Powell DJ Jr, Russell J, Nibu K, Li G, Rhee E, Liao M, Goldstein M, Keane WM, Santoro M, Fusco A, Rothstein JL. The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. Cancer Res. 1998 Dec 1;58(23):5523-8
Alen P, Claessens F, Schoenmakers E, Swinnen JV, Verhoeven G, Rombauts W, Peeters B. Interaction of the putative androgen receptor-specific coactivator ARA70/ELE1alpha with multiple steroid receptors and identification of an internally deleted ELE1beta isoform. Mol Endocrinol. 1999 Jan;13(1):117-28
Heinlein CA, Ting HJ, Yeh S, Chang C. Identification of ARA70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma. J Biol Chem. 1999 Jun 4;274(23):16147-52
Rabes HM, Demidchik EP, Sidorow JD, Lengfelder E, Beimfohr C, Hoelzel D, Klugbauer S. Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clin Cancer Res. 2000 Mar;6(3):1093-103
Tallini G, Asa SL. RET oncogene activation in papillary thyroid carcinoma. Adv Anat Pathol. 2001 Nov;8(6):345-54
Culig Z, Comuzzi B, Steiner H, Bartsch G, Hobisch A. Expression and function of androgen receptor coactivators in prostate cancer. J Steroid Biochem Mol Biol. 2004 Nov;92(4):265-71
Kollara A, Brown TJ. Functional interaction of nuclear receptor coactivator 4 with aryl hydrocarbon receptor. Biochem Biophys Res Commun. 2006 Jul 28;346(2):526-34
Tai PJ, Huang YH, Shih CH, Chen RN, Chen CD, Chen WJ, Wang CS, Lin KH. Direct regulation of androgen receptor-associated protein 70 by thyroid hormone and its receptors. Endocrinology. 2007 Jul;148(7):3485-95
Peng Y, Li CX, Chen F, Wang Z, Ligr M, Melamed J, Wei J, Gerald W, Pagano M, Garabedian MJ, Lee P. Stimulation of prostate cancer cellular proliferation and invasion by the androgen receptor co-activator ARA70. Am J Pathol. 2008 Jan;172(1):225-35
This article should be referenced as such:
de Biase D, Morandi L, Tallini G. NCOA4 (Nuclear Receptor Coactivator 4). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9):654-656.
Identity Other names: 42C, ANX2L, ANX2LG, Annexin II ligand, CAL1L, CLP11, Ca[1], Calpactin, GP11, MGC111133, p10, p11
HGNC (Hugo): S100A10
Location: 1q21.3
Local order: According to NCBI Map Viewer, genes flanking S100A10 in centromere to telomere direction on 1q21 are: THEM4 (1q21) thioesterase superfamily member 4, KRT8P28 (1q21.3) keratin 8 pseudogene 28, S100A10 (1q21) S100 calcium binding protein A10, NBPF18P (1q21.3) neuroblastoma breakpoint family member 18 (pseudogene), S100A11 (1q21) S100 calcium binding protein A11.
DNA/RNA Description The S100A10 gene contains two introns, one in the 5 prime untranslated region of the gene and the other in the protein coding region. The second intron separates the codons for two corresponding amino acids which reside in the sequence connecting the two helix-loop-helix (EF-hand) motifs.
Transcription Transcription produces 7 different mRNAs, 6 alternatively spliced variants and 1 unspliced form.
The mRNAs differ by truncation of the 5' end, alternative splicing or retention of 2 introns.
Pseudogene No known pseudogenes.
Protein Description S100A10 is a member of the S100 family of Ca2+
binding proteins containing 2 EF-hand calcium-binding motifs (Donato, 2001). In contrast to all other S100 proteins, S100A10 is calcium insensitive because of amino acid replacements in its calcium-binding loops that lock the protein in a permanently active state. S100A10 protein is a dimeric protein composed of two 11-kDa subunits (p11 subunits) (Waisman, 1995). S100A10 is found in most cells bound to its annexin II ligand as the heterotetrameric [(S100A10)2 (annexin II)2] complex, also called annexin A2 tetramer (AIIt), in which a central S100A10 dimer interacts with two annexin A2 chains (Lewit-Bentley et al., 2000).
Expression Ubiquitous expression. S100A10 protein is highly expressed in the brain, heart and lung; moderate expression in the liver, bone marrow, spleen, skeletal muscle, pancreas, prostate and kidney.
Localisation Cell surface membrane, Ion channels, membrane of early endosomes and cytoplasm.
S100A10 (S100 calcium binding protein A10) Madureira PA, Waisman DM
Function S100A10 protein plays a key role in the regulation of plasminogen/ plasmin activity. The carboxyl-terminal lysines of S100A10 bind tPA and plasminogen resulting in the stimulation of tPA-dependent plasmin production (MacLeod et al., 2003). Plasmin binds to S100A10 at a distinct site and the formation of the S100A10-plasmin complex stimulates plasmin auto-proteolysis thereby providing a highly localized transient pulse of plasmin activity at the cell surface (MacLeod et al., 2003; Kwon et al., 2005). The binding of tPA and plasmin to S100A10 also protects against inhibition by their physiological inhibitors, PAI-1 and alpha2-antiplasmin, respectively (Kassam et al., 1998). S100A10 also co-localizes plasminogen with the urokinase-type plasminogen activator/(uPA/uPAR) complex thereby localizing and stimulating uPA-dependent plasmin formation to the surface of cancer cells (Kassam et al., 1998). The loss of S100A10 from the extracellular surface of cancer cells results in a significant loss in plasmin generation. In addition, S100A10 knockdown cells demonstrate a dramatic loss in extracellular matrix degradation and invasiveness as well as reduced metastasis (Zhang et al., 2004; Choi et al., 2003). S100A10 has also been shown to be involved in the intracellular trafficking of a set of plasma membrane ion channels and receptors through direct protein interaction. S100A10 has been shown to bind to and regulate the plasma localization of the tetrodotoxin-resistant sodium channel Nav 1.8 (Okuse et al., 2002). Binding of S100A10 to the two-pore domain potassium channel TWIK-related acid sensitive K-1 (TASK 1) protein is important for TASK translocation to the plasma membrane (Renigunta et al., 2006). S100A10 is also involved in the expression of the transient receptor potential (TRP) channels, TRPV5 and TRPV6 at the cell surface (van de Graaf et al., 2003). S100A10 was also shown to bind and regulate the activity of the acid-sensing ion channel ASIC1a (Donier et al., 2005) and the plasma membrane-resident serotonin 5-HT1B receptor (Svenningsson et al., 2006). Increasing evidence suggests that the AIIt protein plays an important role in linking the micro-domain formation to actin rearrangements, either through direct binding to F-actin or through the recruitment of proteins that modulate the actin cytoskeleton (Hayes et al., 2004; Hayes et al., 2006). The AIIt complex recruits the actin-binding protein AHNAK to the
plasma membrane; this protein is involved in the development of the cell membrane cytoarchitecture in polarizing epithelial cells (Benaud et al., 2004; De Seranno et al., 2006).
Homology S100A10 is highly conserved between different species. Human S100A10 has 100% homology to S100A10 from Bos Taurus, Macaca mulatta, Pan troglodytes, Pongo pygmaeus, 98% homology to S100A10 from Canis familiaris, equus caballus, Felis catus, 91% homology to S100A10 from Mus musculus, 88% homology to S100A10 from Rattus norvegicus.
Mutations Note No mutations have been reported for S100A10 that cause congenital anomalies. A recent study tested for rare variants in p11 by resequencing promoter, exonic and flanking intronic regions in 176 Major Depressive Disorder (MDD) cases and 176 matched controls. These studies also assessed common variation by genotyping eight single nucleotide polymorphisms (SNPs), seven tag SNPs and one found through resequencing, in 641 MDD cases and 650 controls. Resequencing revealed nine novel rare variants, including a missense mutation (Asp60Glu) observed in one case and one control, and four variants that occurred only in cases and not controls. The number of rare variants in cases did not exceed that expected by chance for the length of sequence analyzed, and also was not significantly greater than that observed in controls. Resequencing also identified two known SNPs, one (rs4845720) of which was significantly more frequent in MDD cases than controls in the resequenced sample (3.1% vs. 0.9%, P = 0.03), though not in the larger sample (3% vs. 2%, P = 0.15). None of the tag SNPs showed any evidence of association. In conclusion these results did not support a major role for either common or rare p11 SNPs with MDD (Verma et al., 2007).
Implicated in Various cancers Note S100A10 has been shown to be over-expressed a number of different cancers, including thyroid
S100A10 (S100 calcium binding protein A10) Madureira PA, Waisman DM
neoplasms, anaplastic large cell lymphoma, gastric cancer and renal cell carcinoma.
Depressive disorders Note S100A10 knockout mice are viable indicating that S100A10 is not required for normal development. Nevertheless these mice show a depression-like phenotype and reduced responsiveness to serotonin 1B receptor agonists. Moreover, these mice respond less to anti-depressants, suggesting a main role for S100A10 in regulating 5-HT1B receptor function and subsequent depressive disorders (Svenningsson et al., 2006).
References Waisman DM. Annexin II tetramer: structure and function. Mol Cell Biochem. 1995 Aug-Sep;149-150:301-22
Kassam G, Le BH, Choi KS, Kang HM, Fitzpatrick SL, Louie P, Waisman DM. The p11 subunit of the annexin II tetramer plays a key role in the stimulation of t-PA-dependent plasminogen activation. Biochemistry. 1998 Dec 1;37(48):16958-66
Lewit-Bentley A, Réty S, Sopkova-de Oliveira Santos J, Gerke V. S100-annexin complexes: some insights from structural studies. Cell Biol Int. 2000;24(11):799-802
Donato R. S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles. Int J Biochem Cell Biol. 2001 Jul;33(7):637-68
Okuse K, Malik-Hall M, Baker MD, Poon WY, Kong H, Chao MV, Wood JN. Annexin II light chain regulates sensory neuron-specific sodium channel expression. Nature. 2002 Jun 6;417(6889):653-6
Choi KS, Fogg DK, Yoon CS, Waisman DM. p11 regulates extracellular plasmin production and invasiveness of HT1080 fibrosarcoma cells. FASEB J. 2003 Feb;17(2):235-46
MacLeod TJ, Kwon M, Filipenko NR, Waisman DM. Phospholipid-associated annexin A2-S100A10 heterotetramer and its subunits: characterization of the interaction with tissue plasminogen activator, plasminogen, and plasmin. J Biol Chem. 2003 Jul 11;278(28):25577-84
van de Graaf SF, Hoenderop JG, Gkika D, Lamers D, Prenen J, Rescher U, Gerke V, Staub O, Nilius B, Bindels RJ. Functional expression of the epithelial Ca(2+) channels
(TRPV5 and TRPV6) requires association of the S100A10-annexin 2 complex. EMBO J. 2003 Apr 1;22(7):1478-87
Benaud C, Gentil BJ, Assard N, Court M, Garin J, Delphin C, Baudier J. AHNAK interaction with the annexin 2/S100A10 complex regulates cell membrane cytoarchitecture. J Cell Biol. 2004 Jan 5;164(1):133-44
Hayes MJ, Rescher U, Gerke V, Moss SE. Annexin-actin interactions. Traffic. 2004 Aug;5(8):571-6
Zhang L, Fogg DK, Waisman DM. RNA interference-mediated silencing of the S100A10 gene attenuates plasmin generation and invasiveness of Colo 222 colorectal cancer cells. J Biol Chem. 2004 Jan 16;279(3):2053-62
Donier E, Rugiero F, Okuse K, Wood JN. Annexin II light chain p11 promotes functional expression of acid-sensing ion channel ASIC1a. J Biol Chem. 2005 Nov 18;280(46):38666-72
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Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
SEMA4D (sema domain, immunoglobulin domain (Ig), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 4D) John R Basile
Oncology and Diagnostic Sciences University of Maryland, Baltimore Baltimore College of Dental Surgery 650 West Baltimore Street, 7- North Baltimore, Maryland 21201 USA (JRB)
Published in Atlas Database: October 2008
Online updated version : http://AtlasGeneticsOncology.org/Genes/SEMA4DID42255ch9q22.html DOI: 10.4267/2042/44561
DNA/RNA Note Semaphorin 4D (Sema4D) was originally identified by Hall., et al. (1996) as a cell surface protein important in B and T lymphocyte activation. Its expression is upregulated in lymphocytes in an immune response (Kumanogoh et al., 2000; Wang et al., 2001). Sema 4D is also expressed in other tissues where it is involved in many motility responses (for review: Artigiani et al., 1999), including regulation of axonal growth cone guidance (Swiercz et al., 2002), regulation of cell-cell contacts and branching morphogenesis in epithelium (Giordano et al., 2002), promotion of angiogenesis (Basile et al., 2004; Conrotto et al., 2005; Basile et al., 2006), and growth and metastasis of tumors (for review: Neufeld et al., 2005).
Description The gene for Sema4D is located at 9q22.2-q31, a locus that includes PTCH and the xeroderma pigmentosum gene XPA. Sema 4D corresponds to open reading frame 164 and spans the positions 91,181,972 to 91,260,688 on the minus strand.
Transcription The mRNA is 4,675 bp in length.
Protein Note Sema4D is 862 amino acids with a predicted mass of 96.15 kd. Experimentally, Sema4D runs at about 150 kd on a Western blot.
Fig. 1: Sema4D is composed of a Sema domain, a Cystine Rich domain, an Immunoglobulin-like domain, a transmembrane segment and a short cytoplasmic tail.
Description The semaphorins have been shown to exert control over the proliferation and activation of lymphocytes (Hall et al., 1996; Kumanogoh et al., 2001; Wang et al., 2001) (for review: Bismuth et al., 2002), promote tumor growth and metastasis (Christensen et al., 1998) (for review: Kreuter et al., 2002) and regulate development of the lungs (Ito et al., 2000) and the heart and
SEMA4D (sema domain, immunoglobulin domain (Ig), transmembrane domain (TM) Basile JR and short cytoplasmic domain, (semaphorin) 4D)
vasculature (Behar et al., 1996; Brown et al., 2001; Feiner et al., 2001; Torres-Vazquez et al., 2004). There are more than 20 known semaphorins grouped into eight classes: classes 1 and 2 are invertebrate semaphorins, classes 3 to 7 are found in vertebrates, and an eighth class, class V, has been identified in some non-neurotropic DNA viruses (for review: Semaphorin Nomenclature Committee, 1999). Sema4D is composed of a Sema domain, a Cystine Rich domain (also called the Plexin Repeat Domain or the Met Related Sequence), an Immunoglobulin-like domain, and a short cytoplasmic tail (Fig. 1). The Sema domain, a seven-bladed beta-propeller similar in topology to integrins (Love et al., 2003), occurs in the semaphorins and their receptors, the plexins, as well as in the hepatocyte growth factor (HGF) receptor family members Met and RON (for review: Gherardi et al., 2004). The Cystine Rich domain has an unknown function but is found in several different receptors. Three copies of this repeat are found in Plexin-B1, the receptor for Sema4D (Tamagnone et al., 1999), while the Met receptor contains one copy. Immunoglobulin domain family members include components of immunoglobulins and cell surface glycoproteins such as the T-cell receptors CD2, CD4, and CD8. The function of the Sema4D intracellular domain is not known, but it has been associated with a serine kinase activity, suggesting that bi-directional signaling may take place (Elhabazi et al., 1997).
Expression Sema4D is expressed in many tissues including skeletal muscle, blood and bone marrow, lymphoid tissues such as the spleen and thymus, the testes, kidney, small intestine, prostate, heart, placenta, lung, pancreas and the peripheral and central nervous system, as well as in many carcinomas (Basile et al., 2006) and sarcomas (Ch'ng et al., 2007).
Localisation Sema4D is a transmembrane protein bound to the cell surface, though it is sometimes found in a smaller, secreted form (Elhabazi et al., 2001; Basile et al., 2007b; Zhu et al., 2007).
Function Sema4D is expressed on the surface of T, B and dendritic cells and modulates their function through either Plexin-B1 or CD72, a lower affinity receptor for Sema4D found in lymphoid tissues. (Kumanogoh et al., 2000) (for review: Moretti et al., 2006). There is evidence that the HIV-1 Tat protein upregulates the expression of Sema4D in immature dendritic cells, an effect that likely facilitates the expansion of HIV-1 infection (Izmailova et al., 2003). Sema4D also induces collapse of axonal growth cones during neural development and remodeling by binding and activating Plexin-B1 (Oinuma et al., 2004), which is why when many of the semaphorins were first characterized they were referred to as 'collapsins'.
Sema4D is processed into a slightly smaller form that is shed by some cell types. Elhabazi et al. (2001) observed the release of soluble Sema4D from T lymphocytes upon the cleavage of the membrane bound protein at a cysteine residue located immediately adjacent to the transmembrane domain. Zhu, et al. (2007) have demonstrated that platelets express Sema4D, Plexin-B1, and CD72, and that Sema4D is gradually shed from the surface following platelet activation by ADAM17 (also called tumor-necrosis factor-alpha (TNF-a) converting enzyme, or TACE) in a process that promotes formation of a thrombus. Head and neck squamous cell carcinoma cells secrete a soluble form of Sema4D that promotes tumor-induced angiogenesis, in this case cleaved by the membrane type 1-matrix metalloproteinase (MT1-MMP, also called MMP14) (Basile et al, 2006). Upregulation of the MMPs occurs in cancer cells and has, in fact, been linked to the acquisition of an aggressive, more vascular and more invasive phenotype. Ligation of plexins by semaphorins initiates a signaling cascade that involves the G-protein-mediated pathways. For example, Plexin-A1 and Plexin-B1 are known to act as R-Ras GAPs (GTPase-activating proteins) when bound by their respective semaphorins (Oinuma et al., 2004). There is also data to suggest that Plexin-B1 may compete for Rac binding with PAK (p21-activated kinase) (Vikis et al., 2002). Therefore, in addition to inhibiting Ras signaling through its Ras GAP activity, Plexin-B1 may sequester Rac and inhibit PAK activation. The Rho specific GEFs (guanine nucleotide-exchange factors) LARG (leukemia-associated RhoGEF) and PRG (PDZ-RhoGEF) bind to the PDZ-binding motif at the C-terminus of Plexin-B1 and mediate activation of the small GTPase RhoA, and subsequently its downstream effector Rho Kinase (ROK), in response to Sema4D ligation (Driessens et al., 2001; Aurandt et al., 2002; Hirotani et al., 2002; Perrot et al., 2002; Swiercz et al., 2002; Basile et al., 2004; Basile et al., 2007a). Indeed, Sema4D-Plexin-B1 binding contributes to coordination of epithelial-mesenchymal interactions during organogenesis via modulation of RhoA signaling (Korostylev et al., 2008). Plexin-B1-mediated signaling begins with phosphorylation of a tyrosine residue in the intracellular Sex-Plex domain upon Sema4D binding (for review: Castellani et al., 2002). However, it was not known how Plexin-B1 or its downstream target proteins are phosphorylated, since Plexin-B1 is devoid of intrinsic tyrosine kinase activity. A search for the kinase associated with Plexin-B1 revealed that in MLP29 liver progenitor cells, Plexin-B1 interacted with the extracellular domain of the scatter factor receptor tyrosine kinase c-Met (Giordano et al., 2002). In fact, this Plexin-B1/ c-Met interaction may be responsible for a pro-migratory, angiogenic response observed in Sema4D treated endothelial cells (Conrotto et al., 2005) (Fig. 2A). Sema4D-mediated activation of
SEMA4D (sema domain, immunoglobulin domain (Ig), transmembrane domain (TM) Basile JR and short cytoplasmic domain, (semaphorin) 4D)
Plexin-B1 also may promote cell migration by stimulating an intracellular kinase cascade that begins with the recruitment of PDZ RhoGEF and LARG to the C-terminal PDZ binding motif of Plexin-B1. This induces activation of RhoA and ROK and the subsequent phosphorylation and activation of the cytoplasmic tyrosine kinase PYK2, which then phosphorylates Plexin-B1 in the intracellular Sex-Plex domain in a step necessary for a cellular response (Basile et al., 2005) (Fig. 2B). In this model, signaling proceeds through Src, Akt and ERK and results in reorganization of the cytoskeleton (Basile et al., 2005; Aurandt et al., 2006; Basile et al., 2007a)(Fig. 2B). Interestingly, a recent study has shown that inhibition of migration may be elicited by Sema4D under certain conditions where Plexin-B1 preferentially associates with the receptor tyrosine kinase ErbB-2 instead of Met (Swiercz et al., 2008) (Fig. 2C).
Homology Sema4D exhibits homology with the semaphorins and c-Met and the Met-like protein tyrosine kinase RON, receptors collectively known as the scatter factor receptors (for review: Comoglio et al., 1996). The scatter factor receptors participate in branching morphogenesis, axonal guidance in neuronal tissues, and normal and aberrant proliferation and enhanced cell motility in many different cell types (for review: Vande Woude et al., 1997; Maina et al., 1998).
Mutations Note There are no known somatic or germline mutations for Sema4D. Unlike other semaphorins such as Sema3F, whose loss is implicated in lung carcinomas and thus may act as a tumor suppressor (Roche et al., 1996; Tomizawa et al., 2001; Tse et al., 2002),
Fig. 2: Binding of Sema4D to Plexin-B1 via their Sema domains stimulates the tyrosine kinase activity of Met (A) or ErbB-2 (C), resulting in tyrosine phosphorylation of Plexin-B1 in the Sex-Plex domain and initiation of a pro- or anti- migratory response, respectively. Sema4D may also activate an intracellular tyrosine kinase cascade via PDZ RhoGEF or LARG, culminating in a RhoA and ROK-dependent activation of the non-receptor tyrosine kinase PYK2 (B). In turn, PYK2 tyrosine-phosphorylates Plexin-B1 and activates Src, Akt and ERK to elicit a pro-migratory response.
SEMA4D (sema domain, immunoglobulin domain (Ig), transmembrane domain (TM) Basile JR and short cytoplasmic domain, (semaphorin) 4D)
there is no definitive evidence that Sema4D can serve as an oncogene or tumor suppressor.
Implicated in Various tumors Note Acting through Plexin-B1, Sema4D has been shown to promote angiogenesis (Basile et al., 2004; Conrotto et al., 2005; Basile et al., 2006) and also enhance invasive growth and proliferation of tumor cells, while simultaneously offering protection against apoptosis (Granziero et al., 2003; Conrotto et al., 2004; Conrotto et al., 2005). A recent publication shows a correlation between high levels of Sema4D expression in sarcomas and a higher mitotic count, cellularity, and Ki-67 labeling index, when compared to tumors with lower levels of Sema4D expression (Ch'ng et al., 2007). Sema4D is also overexpressed by many different aggressive carcinomas, and its activity on Plexin-B1-expressing endothelial cells promotes enhanced growth and vascularity of tumor xenografts in nude mice in vivo (Basile et al., 2006). Expression of Sema4D by tumor-associated macrophages may also enhance tumor-induced angiogenesis and vessel maturation (Sierra et al., 2008).
Disease There are no known diseases directly related to Sema4D overexpression or mutation. However, in chronic lymphocytic leukemia, there is evidence that Sema4D positive leukemic cells may interact with Plexin-B1-expressing bone marrow stromal cells, follicular dendritic cells, and activated T lymphocytes, resulting in enhanced proliferation and survival of the malignant cells (Granziero et al., 2003). Deletion of the Sema4D locus, which also includes PTCH and XPA, has been observed in the self-healing squamous epithelioma, also known as the keratoacanthoma, and in many squamous cell carcinomas (Waring et al., 1996; Richards et al., 1997; Odeberg et al., 1999), two lesions with a great degree of histological similarity.
Prognosis Higher expression levels of Sema4D are prognostic of poorer overall survival in certain sarcomas (Ch'ng et al., 2007).
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SEMA4D (sema domain, immunoglobulin domain (Ig), transmembrane domain (TM) Basile JR and short cytoplasmic domain, (semaphorin) 4D)
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This article should be referenced as such:
Basile JR. SEMA4D (sema domain, immunoglobulin domain (Ig), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 4D). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9):660-665.
Department of Pathology, New York University School of Medicine, 423 East 23rd St., New York, USA (GD, PL); The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA (ZW)
Published in Atlas Database: October 2008
Online updated version : http://AtlasGeneticsOncology.org/Genes/WDR77ID44142ch1p13.html DOI: 10.4267/2042/44562
Identity Other names: HKMT1069, MEP50, MGC2722, Nbla10071, RP11-552M11.3, p44, p44/Mep50
HGNC (Hugo): WDR77
Location: 1p13.2
DNA/RNA Description Spans 9.3kb/ 7.9kb; 10 exons.
Transcription 2428/ 1029 nucleotides mRNA.
Protein Description 342 amino acids. 44 kDa protein. 5 WD repeats (Hosohata et al., 2003).
Expression p44 is expressed in heart, skeletal muscle, spleen, thymus, prostate, testis, pancreas, and uterus (Hosohata et al., 2003). In adult prostate, p44 is expressed as nuclear protein in glandular epithelial cells and not in stromal cells (Zhou et al., 2006). In testis, p44 expression is seen in germ cells and Leydig cells, but not expressed in peritubular myocytes and Sertoli's cells (Liang et al., 2006).
Localisation p44 has both nuclear and cytolasmic localization patterns (Zhou et al., 2006; Liang et al., 2006; Peng et al., 2008). In benign prostate and testicular cells,
p44 is found predominantly in the nucleus. In prostate cancer and malignant testicular cells (seminomas and leydig cell tumor), p44 is found in the cytoplasm. The p44 cytoplasmic translocation may be an indicative marker of cancer in these tissues.
Function p44 interacts with androgen receptor and acts as a positive coactivator for androgen-dependent AR transactivation (Hosohata, 2003). Nuclear p44 causes an androgen-dependent G1 arrest growth inhibition in prostate cells expressing androgen receptor (Zhou et al., 2006; Peng et al., 2008). Cytoplasmic and nuclear p44 may have opposite functions, as introduction of p44 to the cytoplasm accelerates growth (Peng et al., 2008). p44 is part of the PRMT5 (protein arginine methyl transferase 5) complex important for methylosome activity (Hosohata et al., 2003; Friesen et al., 2002). p44 interacts with FCP1 phosphatase (Licciardo et al., 2002) and histone H2A (Furuno et al., 2006).
Homology WD repeats commonly seen for multiple protein interactions.
Mutations Note Unknown.
Implicated in Androgen-dependent prostate cancer Disease In androgen-dependent prostate cancer p44 is found predominantly in the cytoplasm, as opposed to nuclear
localization in benign tissue (Zhou et al., 2006). Translocation from the nucleus in benign cells to the cytoplasm is strongly associated with prostate tumorigenesis (Zhou et al., 2006; Peng et al., 2008). Cytoplasmic expressed p44 also leads to increased growth in androgen dependent prostate cell line LNCaP (Peng et al., 2008).
Androgen-independent prostate cancer Disease In androgen-independent cancers p44 is found both in the nucleus and the cytoplasm (Peng et al., 2008). P44 may be able to serve as a diagnostic marker of androgen-independent prostate cancer.
Testicular cancer Disease Testicular tumor cells have an increased cytoplasmic localization of p44 similar to the pattern observed in prostate cancer (Jiang et al., 2006). This is also similar to the pattern seen in the germ cells of fetal testis that express cytoplasmic p44. P44 is predominantly found in the nucleus of benign testicular cells and adult testis germ cells. Translocation of p44 to the cytoplasm in testis cells shows an association with tumorigenesis.
References Friesen WJ, Wyce A, Paushkin S, Abel L, Rappsilber J, Mann M, Dreyfuss G. A novel WD repeat protein component of the methylosome binds Sm proteins. J Biol Chem. 2002 Mar 8;277(10):8243-7
Hosohata K, Li P, Hosohata Y, Qin J, Roeder RG, Wang Z. Purification and identification of a novel complex which is involved in androgen receptor-dependent transcription. Mol Cell Biol. 2003 Oct;23(19):7019-29
Licciardo P, Amente S, Ruggiero L, Monti M, Pucci P, Lania L, Majello B. The FCP1 phosphatase interacts with RNA polymerase II and with MEP50 a component of the methylosome complex involved in the assembly of snRNP. Nucleic Acids Res. 2003 Feb 1;31(3):999-1005
Furuno K, Masatsugu T, Sonoda M, Sasazuki T, Yamamoto K. Association of Polycomb group SUZ12 with WD-repeat protein MEP50 that binds to histone H2A selectively in vitro. Biochem Biophys Res Commun. 2006 Jul 7;345(3):1051-8
Zhou L, Wu H, Lee P, Wang Z. Roles of the androgen receptor cofactor p44 in the growth of prostate epithelial cells. J Mol Endocrinol. 2006 Oct;37(2):283-300
Liang JJ, Wang Z, Chiriboga L, Greco MA, Shapiro E, Huang H, Yang XJ, Huang J, Peng Y, Melamed J, Garabedian MJ, Lee P. The expression and function of androgen receptor coactivator p44 and protein arginine methyltransferase 5 in the developing testis and testicular tumors. J Urol. 2007 May;177(5):1918-22
Peng Y, Chen F, Melamed J, Chiriboga L, Wei J, Kong X, McLeod M, Li Y, Li CX, Feng A, Garabedian MJ, Wang Z, Roeder RG, Lee P. Distinct nuclear and cytoplasmic functions of androgen receptor cofactor p44 and association with androgen-independent prostate cancer. Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5236-41
This article should be referenced as such:
Daniels G, Wang Z, Lee P. WDR77 (WD repeat domain 77). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9):666-667.
Dicentric (17;20)(p11.2;q11.2) partial karyotype and ideogram.
Clinics and pathology Disease De novo acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS); treatment-related AML (t-AML) and MDS (t-MDS).
Phenotype/cell stem origin 8 cases reported: 4 de novo AML cases (including one AML-M2 and one erythroleukemia), 3 de novo MDS cases (including one refractory anemia), one t-MDS, and one t-MDS in transformation to AMMoL.
Epidemiology Epidemiology of the 8 patients reported to date, 7 were male and one was female, aged 47 to 87 yreas.
Prognosis Poor; majority of patients died between 2 and 8 months post diagnosis.
Cytogenetics
FISH image of a metaphase showing a normal copy of chromosomes 17 and 20 as well as the dic(17;20). The metaphase appears stained in blue (DAPI counterstain). Red signal, chromosome 20 centromere; green signal: chromosome 17 centromere. The dic(17;20) shows both centromeres.
Additional anomalies Sole anomaly in one case; remaining cases with additional abnormalities; association with -5/del(5q), -7/del(7q), and/or +8 is frequent.
Genes involved and proteins Note dic(17;20) leads to loss of 17p (TP53 gene). Because of
this, patients with this abnormality may have a prognostic outcome similar to the patients with "17p- syndrome". Dicentric (17;20) also leads to loss of 20q [various genes involved: topoisomerase 1 (TOP1), phospholipase C (PLC1), hepatocyte factor nuclear 4 (HNF4), adenosine deaminase (ADA); KRML transcriptional regulator].
References Pedersen B, Kerndrup G. Granulocyte maturation and the chromosome deletion 17p- in primary myelodysplastic syndrome. Acta Haematol. 1990;84(2):77-81
Jary L, Mossafa H, Fourcade C, Genet P, Pulik M, Flandrin G. The 17p-syndrome: a distinct myelodysplastic syndrome entity? Leuk Lymphoma. 1997 Mar;25(1-2):163-8
Watson N, Dunlop L, Robson L, Sharma P, Smith A. 17p- syndrome arising from a novel dicentric translocation in a patient with acute myeloid leukemia. Cancer Genet Cytogenet. 2000 Apr 15;118(2):159-62
Patsouris C, Michael PM, Campbell LJ. A new nonrandom unbalanced t(17;20) in myeloid malignancies. Cancer Genet Cytogenet. 2002 Oct 1;138(1):32-7
Clinics and pathology Disease Childhood pre-B cell acute lymphoblastic leukemia.
Note There is no clinical data in the only paper describing the fusion TCF3-TFPT, nor cytogenetic indications (Brambillasca et al., 1999); inv(19)(p13q13) has also be found in 3 cases of hairy cell leukemia (Haglund et al., 1994); the genes involved in these three patients are unknown; this inv(19) is likely to represent another entity.
Cytogenetics Cytogenetics morphological This chromosome rearrangement is cryptic.
Genes involved and proteins TCF3 Location 19p13.3
Protein TCF3, better known as E2A, is a member of the basic helix-loop-helix (bHLH) 1 family of transcription factors that are ubiquitously expressed during development.
TFPT Location 19q13.4
Protein Role in cell cycle inhibition and apoptosis.
Result of the chromosomal anomaly Hybrid gene Description 5' TCF3 - 3' TFPT; the translocation joins TCF3 exon 13 or 14 to part of TFPT; the junction is in frame in some cases, and out of frame in others. The reciprocal transcript was not found.
Fusion protein Description Variable junction between TCF3 and TFPT, retaining the transactivation domain of TCF3, but with a truncation in TFPT, due to the frequent occurrence of a stop codon.
References Haglund U, Juliusson G, Stellan B, Gahrton G. Hairy cell leukemia is characterized by clonal chromosome abnormalities clustered to specific regions. Blood. 1994 May 1;83(9):2637-45
Brambillasca F, Mosna G, Colombo M, Rivolta A, Caslini C, Minuzzo M, Giudici G, Mizzi L, Biondi A, Privitera E. Identification of a novel molecular partner of the E2A gene in childhood leukemia. Leukemia. 1999 Mar;13(3):369-75
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Isolated tetrasomy 8 in AML, MDS and MPD Olivier Theisen, Jean-Luc Lai, Olivier Nibourel, Catherine Roche-Lestienne
Laboratoire de genetique medicale, hopital Jeanne de Flandre, CHRU de Lille, France (OT, JLL, CRL); Laboratoire d'hematologie, Centre de Biologie et Pathologie, CHRU de Lille, France (ON)
Published in Atlas Database: September 2008
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/Tetra8ID1517.html DOI: 10.4267/2042/44565
Identity Note Isolated tetrasomy 8 is relatively rare compared to trisomy 8. A review of literature revealed only 29 cases of solely tetrasomy 8 in hematologic malignancies. Except for the implication of MLL in AML cases, no additional molecular abnormalities have been explored.
GTG-banding karyotype with isolated tetrasomy 8 in AML-M5.
Clinics and pathology Disease Acute myeloid leukemia (AML)
Phenotype/cell stem origin FAB subtypes: M0 AML (2 cases) M1 AML (1 case) M2 AML (3 cases) M4 AML (3 cases) M5 AML (11 cases out 20).
Epidemiology Median age 56 years (range: 17-82 years); sex ratio: 13M/7F.
Clinics Tetrasomy 8 has been observed in de novo malignant
hemopathies as well as in leukaemia with prior history of haematological disorder (4 cases of myelodisplastic syndrome: 2 RA and 2 RAEB), exposure to radiotherapy or treatment with cytotoxic chemotherapy (1 case of each).
Prognosis Median survival: 15 months.
Disease Myelodysplastic syndrome (MDS)
Phenotype/cell stem origin FAB subtypes: refractory anemia (RA) (1 case), refractory anemia with excess of blasts (RAEB) (1 case), refractory anemia with ringed sideroblasts (RARS) (1 case), chronic myelomonocytic leukemia (CMML) (2 cases) and MF (1 case).
Epidemiology Median age: 68 years (range: 46-91 years); sex ratio: 4M/2F.
Prognosis Median survival: 5.5 months.
Disease Myeloproliferative disorder (MPD)
Phenotype/cell stem origin Subtypes: polycytemia vera (PV) (1 case) and myelofibrosis (MMM) (2 cases).
Epidemiology Median age: 36 years (range 30-51 years); sex ratio: 0M/3F.
Prognosis Median survival: 36 months.
Isolated tetrasomy 8 in AML, MDS and MPD Theisen O, et al.
Probes Specific sequences for the centromere of chromosome 8. No cryptic MLL rearrangements were detected in all cases.
References Jani Sait SN, Raza A, Sandberg AA. Tetrasomy of chromosome 8: an interesting and rare cytogenetic phenomenon in acute nonlymphocytic leukemia. Cancer Genet Cytogenet. 1987 Aug;27(2):269-71
Yoshida J, Nakata K, Oda E, Oda S, Ueyama T, et al. Tetrasomy 8 in acute myelomonocytic leukemia developing after a gastric cancer operation. Cancer Genet Cytogenet. 1991 Jul 1;54(1):27-31
Marosi C, Köller U, Koller-Weber E, Schwarzinger I, et al. Prognostic impact of karyotype and immunologic phenotype in 125 adult patients with de novo AML. Cancer Genet Cytogenet. 1992 Jul 1;61(1):14-25
Flactif M, Lai JL, Deminatti MM. A new case of isolated tetrasomy of chromosome 8 in a patient with therapy-related myelodysplastic syndrome: confirmation by chromosome painting in metaphase and interphase nuclei. Cancer Genet Cytogenet. 1993 Feb;65(2):175-6
Marosi C, Muhm M, Argyriou-Tirita A, Pehamberger H, Pirc-Danoewinata H, Geissler K, Locker G, Grois N, Haas OA. Tetrasomy 8 in acute monoblastic leukemia (AML-M5a) with myelosarcomatosis of the skin. Cancer Genet Cytogenet. 1993 Nov;71(1):50-4
Wullich B, Koch B, Schwarz M, Lindemann U, Pfreundschuh M, Zang KD. A further case of acute nonlymphocytic leukemia with tetrasomy 8. Cancer Genet Cytogenet. 1993 Sep;69(2):126-8
Miranda RN, Mark HF, Medeiros LJ. Fluorescent in situ hybridization in routinely processed bone marrow aspirate clot and core biopsy sections. Am J Pathol. 1994 Dec;145(6):1309-14
Trautmann U, Gramatzki M, Krauss M, Friz A, Liehr T, Gebhart E. Tetrasomy 8 as a clonal anomaly in myeloid neoplasias. Cancer Genet Cytogenet. 1994 Feb;72(2):101-4
Cull GM, Howe DJ, Stack-Dunne M, Phillips MJ, Johnson SA. Tetrasomy of chromosome 8 in a patient with acute myeloid leukemia. Leuk Lymphoma. 1995 Oct;19(3-4):355-8
Solé F, de Pablos JM, Woessner S, Pérez MM, Jurado M, Espinet B, Grao P, Moratalla A, Esquivias J. Coexistence of tetrasomy 8 and trisomy 8 in a case with myeloid metaplasia with myelofibrosis. Cancer Genet Cytogenet. 1997 Apr;94(2):147-50
Xue Y, Guo Y, Zhou Y, Xie X, Zheng L, Shen M. Isolated tetrasomy 8 in minimally differentiated acute myeloid leukemia (AML-M0). Leuk Lymphoma. 1999 May;33(5-6):581-5
Ferro MT, Vázquez-Mazariego Y, Ramiro S, et al. Trisomy/ tetrasomy of chromosome 8 and +i(8q) as the sole chromosome abnormality in three adult patients with myelomonocytic leukemia. Cancer Genet Cytogenet. 2000 Jul 15;120(2):163-5
Kameoka J, Funato T, Obara Y, Kadowaki I, et al. Clonal evolution from trisomy into tetrasomy of chromosome 8 associated with the development of acute myeloid leukemia from myelodysplastic syndrome. Cancer Genet Cytogenet. 2001 Jan 15;124(2):159-64
Yan J, Marceau D, Drouin R. Tetrasomy 8 is associated with a major cellular proliferative advantage and a poor prognosis. two cases of myeloid hematologic disorders and review of the literature. Cancer Genet Cytogenet. 2001 Feb;125(1):14-20
Beyer V, Mühlematter D, Parlier V, Cabrol C, et al. Polysomy 8 defines a clinico-cytogenetic entity representing a subset of myeloid hematologic malignancies associated with a poor prognosis: report on a cohort of 12 patients and review of 105 published cases. Cancer Genet Cytogenet. 2005 Jul 15;160(2):97-119
Kim J, Park TS, Song J, Lee KA, Lee SG, Cheong JW, Choi JR. Tetrasomy 8 in a patient with acute monoblastic leukemia. Korean J Lab Med. 2008 Aug;28(4):262-6
This article should be referenced as such:
Theisen O, Lai JL, Nibourel O, Roche-Lestienne C. Isolated tetrasomy 8 in AML, MDS and MPD. Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9):671-672.
Myelodysplastic syndrome ( MDS ) type refractory anemia (RA) (Wlodarska et al., 1995) and refractory anemia with excess blasts (RAEB) (Struski et al., 2008). Philadelphia chromosome positive chronic myeloid leukemia (CML) in transformation (Aguiar et al., 1997).
Etiology Only 3 cases so far; 77-year old male (MDS-RA) and 71-year old female (MDS-RAEB). No data available on a case of CML.
Prognosis Unknown so far.
Cytogenetics Cytogenetics molecular FISH demonstrated ETV6 involvement in both MDS cases. In a case of CML, the 12p13 breakpoint was mapped between ETV6 (11.9 Mb) and GDID4 (15 Mb). In addition, FISH detected a cryptic deletion of CDKN1B (12.7 Mb) associated with this translocation.
Additional anomalies The translocation was found as a sole aberration in a case of MDS-RA, in a subclone with del(5)(q13q34) in a case of MDS-RAEB, and was accompanying t(9;22)(q34;q11) in a case of CML.
Variants The ETV6-involving t(10;12)(q24;p13) was recognized as the first variant of t(5;12)(q33;p13) targeting ETV6 and PDGFRB (Wlodarska et al., 1995) (Golub et al., 1994). So far, at least 24 ETV6-associated fusion transcripts have been identified in human malignancies.
FISH with cosmids specific for the 5' end (c179A6) and the 3' end (c148B6) of ETV6 in a case of MDS-RA (Wlodarska et al., 1995).
Genes involved and proteins ETV6 Location 12p13.2
DNA/RNA ETV6 encodes an ets (E-26 transforming specific) family transcription factor. Three transcripts have been described: ETV6-202 (8 exons; length 5.974 bps; 452 amino acids), ETV6-203 (10 exons; length 5.697 bps; 451 amino acids) and ETV6-201 (5 exons; length 1836 bps; 61 amino acids). Transcription is from telomere to centromere.
Protein Two functional domains have been indentified: a N-terminal Helix-Loop-Helix domain (or pointed (PNT) or Sterile Alpha Motif (SAM) domain) responsible for hetero- and homodimerization with itself and possibly other proteins, and a C-terminal ETS domain responsible for a specific DNA binding. HLH domain is encoded by exons 3 and 4, and ETS domain by exons 6-8. As a transcription regulator, ETV6 is localized in the nucleus. Experimental data suggest that ETV6 is required for hematopoiesis and maintenance of the developing vascular network.
GOT1 Location 10q24
DNA/RNA 9 exons; transcript of 10942 bps. Transcription is from telomere to centromere.
Protein GOT1 encodes for a cytosolic form of an ubiquitous pyridoxal phosphate-dependent enzyme. The enzyme plays an important role in amino acid metabolism and in the urea and tricarboxylic acid cycles. The GOT1 protein is 413-amino acid long and its predicted molecular weight is 46 kDA.
Result of the chromosomal anomaly Hybrid gene Note Molecular consequences of the seemingly looking t(10;12)(q24;p13) found in MDS and CML seem to be different.
Description Both MDS cases showed the ETV6-GOT1 transcript formed by an in frame fusion between the first two exons of ETV6 and exon 2 to exon 9 of GOT1 (MDS-RA), or by fusion of exon 3 of ETV6 with exon 2 of GOT1 (MDS-RAEB). In both cases additional not-in frame fusions involving ETV6 and sequences telomeric to GOT1 have been identified. The t(10;12) found in a case of CML in transformation does not involve ETV6; the 12p13 breakpoint was mapped between ETV6 and GDID4. Whether this translocation results in an in frame fusion or is a bystander event associated with the deletion of CDKN1B detected in this case is unknown.
Fusion protein Description The molecular consequences of the ETV6-GOT1
fusion remain unclear. It has been postulated that the fusion protein, only lacking a short N-terminal part of GOT1, can still form heterodimers with wild type GOT1, thereby acting as a dominant negative form, resulting in a reduction of GOT1 enzymatic activity in dysplastic cells. In addition, the translocation could also deregulate the expression of genes located upstream of GOT1 (e.g. c10orf139, found to be overexpressed in the MDS-RA case) or leads to inactivation of ETV6.
References Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell. 1994 Apr 22;77(2):307-16
Wlodarska I, Mecucci C, Marynen P, Guo C, Franckx D, La Starza R, Aventin A, Bosly A, Martelli MF, Cassiman JJ. TEL gene is involved in myelodysplastic syndromes with either the
typical t(5;12)(q33;p13) translocation or its variant t(10;12)(q24;p13). Blood. 1995 May 15;85(10):2848-52
Aguiar RC, Chase A, Oscier DG, Carapeti M, Goldman JM, Cross NC. Characterization of a t(10;12)(q24;p13) in a case of CML in transformation. Genes Chromosomes Cancer. 1997 Dec;20(4):408-11
Janssen H, Wlodarska I, Mecucci C, Hagemeijer A, Vandenberghe P, Marynen P, Cools J. Fusion of ETV6 to GOT1 in a case with myelodysplastic syndrome and t(10;12)(q24;p13). Haematologica. 2006 Jul;91(7):949-51
Struski S, Mauvieux L, Gervais C, Hélias C, Liu KL, Lessard M. ETV6/GOT1 fusion in a case of t(10;12)(q24;p13)-positive myelodysplastic syndrome. Haematologica. 2008 Mar;93(3):467-8
This article should be referenced as such:
Wlodarska I. t(10;12)(q24;p13). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9):673-675.
Clinics and pathology Disease Myeloproliferative disease evolving towards a M5-AML; the t(4;21) may be therapy related.
Epidemiology Only one case to date, a female patient aged 74 years (Jeandidier et al., 2006).
Cytogenetics Additional anomalies Unrelated clones; one of which with +8, another one with +21.
Genes involved and proteins Note The partner of RUNX1 is unknown.
RUNX1 Location 21q22
Protein Contains a Runt domain and, in the C-term, a transactivation domain; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes.
References Jeandidier E, Dastugue N, Mugneret F, Lafage-Pochitaloff M, Mozziconacci MJ, Herens C, Michaux L, Verellen-Dumoulin C, Talmant P, Cornillet-Lefebvre P, Luquet I, Charrin C, Barin C, Collonge-Rame MA, Pérot C, Van den Akker J, Grégoire MJ, Jonveaux P, Baranger L, Eclache-Saudreau V, Pagès MP, Cabrol C, Terré C, Berger R. Abnormalities of the long arm of chromosome 21 in 107 patients with hematopoietic disorders: a collaborative retrospective study of the Groupe Français de Cytogénétique Hématologique. Cancer Genet Cytogenet. 2006 Apr 1;166(1):1-11
Clinics and pathology Disease De novo acute myeloid leukemia (AML), type M2 with monocytosis or M4 in the case tested for RUNX1. Other cases presented with a chronic myelomonocytic leukemia evolving towards a M4-AML which may be therapy related, and with a M3-AML (promyelocytic leukemia) with t(15;17).
Epidemiology Only three cases to date, 2 male and 1 female patients, aged 46, 70, ? (Koo et al., 1998; Jeandidier et al., 2006).
Cytogenetics Additional anomalies Sole anomaly in one case, presence of an unrelated clone in another. The t(7;21) accompanied the classical t(15;17)(q22;q11) in the M3-AML.
Genes involved and proteins Note The partner of RUNX1 is unknown.
RUNX1 Location 21q22
Protein Contains a Runt domain and, in the C-term, a transactivation domain; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes.
References Koo SH, Kwon GC, Chun HJ, Park JW. Cytogenetic and fluorescence in situ hybridization analyses of hematologic malignancies in Korea. Cancer Genet Cytogenet. 1998 Feb;101(1):1-6
Jeandidier E, Dastugue N, Mugneret F, Lafage-Pochitaloff M, Mozziconacci MJ, Herens C, Michaux L, Verellen-Dumoulin C, Talmant P, Cornillet-Lefebvre P, Luquet I, Charrin C, Barin C, Collonge-Rame MA, Pérot C, Van den Akker J, Grégoire MJ, Jonveaux P, Baranger L, Eclache-Saudreau V, Pagès MP, Cabrol C, Terré C, Berger R. Abnormalities of the long arm of chromosome 21 in 107 patients with hematopoietic disorders: a collaborative retrospective study of the Groupe Français de Cytogénétique Hématologique. Cancer Genet Cytogenet. 2006 Apr 1;166(1):1-11
Identity Note Osteochondroma (osteocartilaginous exostosis) is a cartilage capped bony neoplasm arising on the external surface of bone containing a marrow cavity that is continuous with that of the underlying bone. It arises in bones preformed by endochondral ossification and the most common site of involvement is the metaphyseal region of the long bone of the limbs, like the distal femur, upper humerus, upper tibia and fibula. They also frequently occur in the flat bones, in particular the ilium and scapula. Osteochondromas can occur as a solitary lesion (solitary osteochondromas) or within the context of Multiple Osteochondromas (MO). The literature indicates slight male sex predominance (male/female ratio 1.5:1). Most osteochondromas are prone to arise in the first 3 decades of life. Osteochondromas hardly occur in the craniofacial bones. This might be explained by the fact that these bones are not formed by endochondral ossification.
Clinics and pathology Epidemiology Osteochondromas are the most common benign bone tumors. They represent 35% of the benign and 8% of all bone tumours, although this is probably an underestimation since the majority are asymptomatic. Approximately 15% of patients with osteochondromas have multiple osteochondromas (MO).
Clinics The growth of the osteochondroma ceases at skeletal maturation or shortly thereafter. Patients may have a swelling of year's causing symptoms related to the location and site of the lesion such as mechanical obstruction, nerve impingement, pseudoaneurysm of an overlying vessel, fracture at the stalk of the lesion, or the formation of a bursa over the osteochondroma. However most lesions are asymptomatic and found accidentally. The most serious complication is malignant transformation towards secondary peripheral chondrosarcoma, which is estimated to occur in <1% of solitary cases and 0.5-5% of MO cases.
Pathology Pedunculated osteochondromas contain a stalk and are long and slender, while sessile ones are flat. Many osteochondromas are cauliflower shaped (figure 1). A fibrous perichondrium covers the cartilage cap and is continuous with the periosteum of the underlying bone. The cartilage cap is less than 2 cm thick and this is decreasing with age. A thick (greater than 2 cm) and irregular cap may indicate malignant transformation of the tumor. The cap covers the entire elevated surface of a sessile tumor, while it only covers the distal part of a pedunculated one. The cartilage cap merges into the underlying spongiosa. Here the chondrocytes are arranged according to an epiphyseal growth plate. A typical benign chondrocyte has a single small nucleus. During active bone growth, binucleated chondrocytes may be seen in benign tumors.
Figure 1: Histological appearance of an osteochondroma. A perichondrium (Bellaiche et al., 1998) covers the cartilage cap (Bernard et al., 2001). The cap merges into the underlying spongiosa (Bornemann et al., 2004), where the chondrocytes are arranged according to an epiphyseal growth plate (Bovée et al., 1999). The spongiosa of the stalk is continuous with the underlying cancellous bone. Fractures within the stalk may produce fibroblastic proliferation and even new bone formation. A bursa may develop over the osteochondroma and is usually attached to the perichondrium of the cap. The bursal wall is lined by synovium that may show inflammatory changes.
Treatment The low rate of malignant transformation (<1%) is insufficient reason for resection. Osteochondromas are usually removed for cosmetic reasons, when symptoms of pain, limitation of motion, or impingement on adjacent structures such as nerves and blood vessels occur, or when roentogenographic features or an abnormal increase in tumor size suggest progression towards malignancy. When surgical resection is needed, the entire lesion should be removed, including the complete cartilaginous cap, to avoid recurrence. Multiple recurrence or recurrence in a well-excised lesion should raise suspicion of malignancy.
Evolution Until recently, there has been a lot of debate about whether an osteochondroma is a developmental disorder or a true neoplasm. It was for long considered to be a perversion in the direction of bone growth. However, recent studies have shown osteochondroma to be a true neoplasm, since presence of loss of heterozygosity (LOH) and aneuploidy in osteochondromas indicate a clonal origin for the cartilaginous tissue of osteochondromas. Inactivation of both alleles of EXT1 in cartilaginous cells of the cap is required for the formation of solitary and multiple osteochondromas.
Prognosis Complete excision of osteochondroma is usually curative. Failure to remove the entire cartilaginous cap or its overlying periosteum is the basis for most recurrences. Recurrence could also suggest malignancy.
Cytogenetics Note Cytogenetic aberrations involving 8q22-24.1, where the EXT1 gene is located, have been found in ten out of 30 sporadic and in 1 out of 13 multiple osteochondromas. In one sporadic case deletion of 11p11-12 was found. In 7 out of 8 solitary osteochondromas homozygous deletions of EXT1 were identified. Aberrations of chromosome 1p (1p13-p22) were found in five of seven osteochondromas.
Cytogenetics Molecular Loss of heterozygosity (LOH) was found almost exclusively at the EXT1 locus in both sporadic and multiple osteochondromas using microsatellite analysis. Fluorescence in situ hybridization revealed loss of the 8q24 locus. The EXT genes, involved in MO, are hypothesized to be tumor suppressor genes. Germline EXT1 mutations, resulting in a truncated EXT1 protein, together with the loss of the remaining wild type allele was demonstrated in both sporadic and multiple osteochondromas. These findings suggest that inactivation of both copies of the EXT1 gene is required for the development of osteochondromas. The EXT proteins are involved in the biosynthesis of heparan sulphate (HS). Heparan sulphate proteoglycans
(HSPG) are large macromolecules composed of heparan sulphate glycosaminoglycan chains linked to a protein core. Four HSPG families are syndecan, glypican, perlecan and isoforms of CD44. HSPGs are required for high-affinity binding of fibroblast growth factor to its receptor. Furthermore, studies in Drosophila have shown that EXT (tout-velu, Ttv) is required for the diffusion of the morphogens: Hedgehog (Hh, human homologues Indian Hedgehog (IHh) and Sonic Hedgehog (SHh), decapentaplegic (dpp, human homologues TGB-beta and BMP) and wingless (human homologue Wnt). It was therefore hypothesized that EXT mutations affect IHh/PTHLH, TGF-beta/BMP and Wnt signaling pathways within the normal growth plate. Indeed, altered levels of the EXT1 and EXT2 protein and of their putative downstream effectors (IHh/PTHrP, TGF-beta/BMP and Wnt signalling pathways) were demonstrated in both solitary and multiple osteochondromas. In addition, due to impaired EXT1/EXT2 function the HSPGs appear to be retained in the Golgi apparatus and cytoplasm of the tumour cell, instead of being transported to the cell surface and/or extra cellular matrix where they normally exert their function. Moreover, EXT mutations were described to induce cytoskeletal abnormalities (altered actin distribution) in osteochondroma chondrocytes. Malignant transformation of osteochondroma is characterized at the DNA level by chromosomal instability, as demonstrated by a high percentage of LOH and aneuploidy in chondrosarcomas compared to LOH restricted to 8q24 and diploidy or mild aneuploidy in osteochondroma. At the protein level, upregulation of PTHrP and BCL2 is found in grade I peripheral chondrosarcomas as compared to osteochondromas.
References Mertens F, Rydholm A, Kreicbergs A, Willén H, Jonsson K, Heim S, Mitelman F, Mandahl N. Loss of chromosome band 8q24 in sporadic osteocartilaginous exostoses. Genes Chromosomes Cancer. 1994 Jan;9(1):8-12
Unni KK.. Chondrosarcoma (Primary, Secondary, Dedifferentiated, and Clear Cell). Dahlin's bone tumors. General aspects and data on 11,087 cases. 1996; pp 71-108.
Bellaiche Y, The I, Perrimon N. Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion. Nature. 1998 Jul 2;394(6688):85-8
Bridge JA, Nelson M, Orndal C, Bhatia P, Neff JR. Clonal karyotypic abnormalities of the hereditary multiple exostoses chromosomal loci 8q24.1 (EXT1) and 11p11-12 (EXT2) in patients with sporadic and hereditary osteochondromas. Cancer. 1998 May 1;82(9):1657-63
Bovée JV, Cleton-Jansen AM, Wuyts W, Caethoven G, Taminiau AH, Bakker E, Van Hul W, Cornelisse CJ, Hogendoorn PC. EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. Am J Hum Genet. 1999 Sep;65(3):689-98
Bovée JV, van den Broek LJ, Cleton-Jansen AM, Hogendoorn PC. Up-regulation of PTHrP and Bcl-2 expression characterizes the progression of osteochondroma towards peripheral chondrosarcoma and is a late event in central chondrosarcoma. Lab Invest. 2000 Dec;80(12):1925-34
Geirnaerdt MJ, Hogendoorn PC, Bloem JL, Taminiau AH, van der Woude HJ. Cartilaginous tumors: fast contrast-enhanced MR imaging. Radiology. 2000 Feb;214(2):539-46
Bernard MA, Hall CE, Hogue DA, Cole WG, Scott A, Snuggs MB, Clines GA, Lüdecke HJ, Lovett M, Van Winkle WB, Hecht JT. Diminished levels of the putative tumor suppressor proteins EXT1 and EXT2 in exostosis chondrocytes. Cell Motil Cytoskeleton. 2001 Feb;48(2):149-62
Hecht JT, Hall CR, Snuggs M, Hayes E, Haynes R, Cole WG. Heparan sulfate abnormalities in exostosis growth plates. Bone. 2002 Jul;31(1):199-204
Sawyer JR, Thomas EL, Lukacs JL, Swanson CM, Ding Y, Parham DM, Thomas JR, Nicholas RW. Recurring breakpoints of 1p13 approximately p22 in osteochondroma. Cancer Genet Cytogenet. 2002 Oct 15;138(2):102-6
Bornemann DJ, Duncan JE, Staatz W, Selleck S, Warrior R. Abrogation of heparan sulfate synthesis in Drosophila disrupts the Wingless, Hedgehog and Decapentaplegic signaling pathways. Development. 2004 May;131(9):1927-38
Hameetman L, David G, Yavas A, White SJ, Taminiau AH, Cleton-Jansen AM, Hogendoorn PC, Bovée JV. Decreased EXT expression and intracellular accumulation of heparan sulphate proteoglycan in osteochondromas and peripheral chondrosarcomas. J Pathol. 2007 Mar;211(4):399-409
Hameetman L, Szuhai K, Yavas A, Knijnenburg J, van Duin M, van Dekken H, Taminiau AH, Cleton-Jansen AM, Bovée JV, Hogendoorn PC. The role of EXT1 in nonhereditary osteochondroma: identification of homozygous deletions. J Natl Cancer Inst. 2007 Mar 7;99(5):396-406
Clinics and pathology Disease A subset of non-small cell lung cancer harbors the EML4-ALK fusion gene. Incidence of such tumors is 4-5% in non-small cell lung cancer among the Asian ethnic group, but may be lower among the others.
Genetics Note Vast majority of EML4-ALK positive lung cancer is negative for active EGFR and active KRAS.
Cytogenetics Note inv(2)(p21p23)
Genes involved and proteins Note Inv(2)(p21p23) involves EML4 and ALK, generating the EML4-ALK and ALK-EML4 fusion genes.
EML4 Location 2p21
Protein 981 amino acids; 109 kDa; microtubule associated protein.
ALK Location 2p23
Protein 1620 amino acids; 176 kDa; membrane-associated tyrosine kinase receptor.
Result of the chromosomal anomaly Hybrid Gene Note In lung cancer cells, 5'-part of EML4 is fused to intron 19 of ALK, generating EML4-ALK. While intron 19 of ALK is involved in the rearrangement in most of the cases, breakpoints within EML4 may diverge, giving rise to various isoforms of EML4-ALK. Detailed information of known variants is shown below. EML4-ALK(E13;A20): Intron 13 of EML4 is ligated to intron 19 of ALK, generating an EML4-ALK mRNA where exon 13 of the former is fused to exon 20 of the latter (also referred to as variant 1). EML4-ALK(E20;A20): Intron 20 of EML4 is ligated to intron 19 of ALK, generating an EML4-ALK mRNA where exon 20 of the former is fused to exon 20 of the latter (also referred to as variant 2). EML4-ALK(E6;A20): Intron 6 of EML4 is ligated to intron 19 of ALK, generating an EML4-ALK mRNA where exon 6a of the former is fused to exon 20 of the latter. Alternative splicing of the messages gives rise to the E6a; A20 (variant 3a) and E6b; A20 (variant 3b) mRNAs, which contains exon 6a and 6a+6b of EML4, respectively. EML4-ALK(E14;ins11;del49A20): Another rearrangement generates an EML4-ALK mRNA where exon 14 of EML4 is ligated to a fragment of 11 bp with
Lung: non-small cell carcinoma with inv(2)(p21p23) Mano H
unknown origin, and in turn connected to a nucleotide at position 50 of exon 20 of ALK (also referred to as variant 4 by Takeuchi et al.). EML4-ALK(E15del19;del20A20): Another rearrangement generates an EML4-ALK mRNA where a part of exon 15 of EML4 is fused to a nucleotide at position 21 of exon 20 of ALK (also referred to as variant 4 by Koivunen et al.). EML4-ALK(E2;A20) and EML4-ALK(E2;add117A20): Intron 2 of EML4 is ligated to intron 19 of ALK, generating an EML4-ALK mRNA where exon 2 of the former is fused to exon 20 of the latter (also referred to as variant 5a). From the same gene rearrangement, alternative splicing of messages further generates an mRNA where exon 2 of EML4 is connected to a position within intron 19 of ALK located 117 bp-upstream of exon 20 (also referred to as variant 5b).
Fusion Protein Note All EML4-ALK fusion mRNAs encode proteins where a part of EML4 is fused to the cytoplasmic kinase domain of ALK. The amino-terminal coiled-coil domain within EML4 is necessary and sufficient for the transforming activity of EML4-ALK, probably through oligomerazing the fusion proteins.
References Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y, Hu Y, Tan Z, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007 Dec 14;131(6):1190-203
Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007 Aug 2;448(7153):561-6
Choi YL, Takeuchi K, Soda M, Inamura K, Togashi Y, Hatano S, Enomoto M, Hamada T, Haruta H, Watanabe H, Kurashina K, Hatanaka H, Ueno T, Takada S, Yamashita Y, Sugiyama Y, Ishikawa Y, Mano H. Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer. Cancer Res. 2008 Jul 1;68(13):4971-6
Inamura K, Takeuchi K, Togashi Y, Nomura K, Ninomiya H, Okui M, Satoh Y, Okumura S, Nakagawa K, et al. EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. J Thorac Oncol. 2008 Jan;3(1):13-7
Koivunen JP, Mermel C, Zejnullahu K, Murphy C, Lifshits E, Holmes AJ, Choi HG, Kim J, Chiang D, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res. 2008 Jul 1;14(13):4275-83
Takeuchi K, Choi YL, Soda M, Inamura K, Togashi Y, Hatano S, Enomoto M, Takada S, Yamashita Y, Satoh Y, Okumura S, Nakagawa K, Ishikawa Y, Mano H. Multiplex RT-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res. 2008; in press.
This article should be referenced as such:
Mano H. Lung: non-small cell carcinoma with inv(2)(p21p23). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9):681-682.
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Ovary: Choriocarcinoma Eiko Yamamoto
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya city, Aichi pref 466-8550, Japan (EY)
Published in Atlas Database: September 2008
Online updated version : http://AtlasGeneticsOncology.org/Tumors/OvaryChoriocarcID5219.html DOI: 10.4267/2042/44571
Identity Alias Choriocarcinoma of the ovary; Ovarian choriocarcinoma
Note Choriocarcinoma of the ovary is a highly malignant ovarian tumor which is characterized pathologically by the presence of trophoblastic malignant cells, and biochemically by the production of the pregnancy hormone human chorionic gonadotrophin (hCG) in the absence of an ongoing pregnancy. Choriocarcinoma tends to be invasive and to metastasize early and widely through both the venous and lymphatic systems. This disease is classified two types in origin, gestational choriocarcinoma and nongestational germ cell tumor. Nongestational pure choriocarcinoma is so rare that the prognosis, chemo-sensitivity, and genetics analysis of nongestational type have not been decided compared with that of gestational type. It is necessary, but difficult to distinguish nongestational choriocarcinoma from gestational choriocarcinoma except by DNA analysis.
Classification Classification of choriocarcinoma of the ovary is based on gestational or not. It is very difficult to differentiate a pure ovarian carcinoma with a non-gestational origin from a gestational one using histopathological investigation. It can be diagnosed with only in a patient who is sexually immature, unable to conceive, or has never had sexual intercourse, unless DNA analysis is not performed. The gestational type includes an ovarian metastasis from primary uterine choriocarcinoma which occurs in association with a normal pregnancy or spontaneous abortion, complete hydatidiform mole, or partial mole,
and primary gestational ovarian choriocarcinoma which arises from ectopic pregnancy in the ovary. The nongestational type is as a component of a mixed germ cell tumor and a pure ovarian choriocarcinoma is a very rare malignant tumor.
Clinics and pathology Etiology By far the most important risk factor for gestational choriocarcinoma is the nature of the preceding pregnancy. A hydatidiform mole carries with it a 1,000 - to 2,000 fold increased risk of choriocarcinoma, one of the most striking cancer risk factors identified in humans. In nongestational choriocarcinoma, no factors have been associated with the etiology of germ cell tumor, apart from an increased incidence associated with dysgenetic gonads.
Epidemiology Gestational type Women over the age of 40 are at increased risk for gestational choriocarcinoma. The reported prevalence of choriocarcinoma varies widely throughout the world, being greatest in Asia, Africa, and Latin America and substantially lower in North America, Europe, and Australia. Choriocarcinoma occurs with a frequency of 1:20,000 to 1:40,000 pregnancies in the United States and Europe. Estimates for the incidence in Asia, Africa, and Latin America have generally been higher; rates as high as 1 per 500 to 1,000 pregnancies have been reported, although marked regional variations do occur. Gestational choriocarcinoma follows normal pregnancy (25%), spontaneous abortion (25%), and hydatidiform mole (50%), but only about 3-5% of all molar pregnancies eventuate in choriocarcinoma. Gestational
primary ovarian choriocarcinoma is extremely rare, with an estimated incidence of 1 in 3.7 x 108 pregnancies. Nongestational type Nongestational choriocarcinoma arises in women under 40 years old because of germ cell tumor, and the frequency is reported less than 0.6% of all ovarian tumors. Goswami et al. reported the mean age 13.6 +/- 6.9 years old.
Clinics Clinical symptoms are variety in gestational type, because choriocarcinoma is likely to metastasis to multiple organs, such as lung, liver, and brain. More than 90% of patients with extrauterine gestational choriocarcinoma will have lung metastasis. In nongestational type, predominant presenting symptom is lower abdominal pain. Common complains includes atypical genital bleeding, amenorrhea, nausea, and vomiting because of high level of hCG. Choriocarcinoma is often diagnosed by the finding of an elevated hCG level in association with metastatic lesion detected radiaographically. The levels of serum or urine beta-hCG are good tumor marker for the progression or remission of disease.
Pathology There is no difference in pathological appearances between gestational type and nongestational pure choriocarcinoma. On gross examination, a circumscribed hemorrhagic mass is observed. Microscopically, hemorrheage and necrosis are found, and tumor cells resemble placental trophoblastic cells: cytotrophoblast (CT), intermediate trophoblast (IT), and syncytiotrophoblast (ST). The CT and IT tend to grow in clusters and sheets separated by ST. The typical pattern of choriocarcinoma has been called "two cell pattern", "biphasic"-terms that reflect the relatively regular, alternating arrangement of CT and ST in the tumor interspread with intermediate trophoblast. Nuclear plemorphism, hyperchromasia and nuclei are prominent. Immunohistochemically, beta-hCG is expressed in syncytiotrophoblastic cells, but not cytotrophoblastic cells.
Treatment Gestational choriocarcinoma is treated with methotrexate-based chemotherapy, for example MEA (methotrexate, etoposide and actinomycin-D), EMA/CO (methotrexate, etoposide, actinomycin-D, cyclophosphamide and vincristine), or EP/EMA (etoposide, cisplatin, methotrexate and actinomycin-D). However, nongestational ovarian choriocarcinoma (germ cell tumor) is so rare that there is lack information on therapeutic options. Germ cell tumors of the ovary are treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy. A complete staging operation is indispensable for management and prognostication. In young patients,
stage I germ cell tumors can be treated with conservative surgery, i.e., unilateral oophorectomy or salpingo-oophorectomy. Postoperative chemotherapy is recommended by combination chemotherapy with the BEP (bleomycin, etoposide and cisplatin) or methotrexate-based regimen.
Prognosis The prognosis of gestational choriocarcinoma is getting better by advances of combination chemotherapy. The survival rate is increasing and 96.4% in 15 years since 1985. Nongestational pure choriocarcinoma of the ovary is so rare that it is not known whether the prognosis is worse than gestational choriocarcinoma or not. Some papers reported that nongestational choriocarcinoma of the ovary has worse prognosis and is less sensitive to methotrexate-based chemotherapeutic regimens than gestational neoplasm. But they did not diagnose definitely by DNA polymorphism analysis. It is important to clarify whether the tumor arose from a gestational or nongestational origin in order to understand the prognosis of this disease accurately.
Genetics Note To differentiate gestational from nongestational tumors, it is necessary to determine whether a paternal contribution is present in the genome of the tumor. Examination of genetic polymorphisms from the tumor and comparison with those found in the patient and her partner should define the presence or absence of paternal DNA and establish whether or not a tumor is gestational. An extensive literature search including Medline demonstrated only five reported cases of nongestational ovarian pure choriocarcinoma diagnosed with DNA polymorphic analysis from 1985 to 2007.
Cytogenetics Note Gestational choriocarcinoma shows wider variations in karyotype, most being aneuploid, with some in the hyperdiploid and hypotetraploid range. Many forms of chromosomal gains, losses and rearrangements are observed, but no specific chromosomal abnormality has yet been identified.
Cytogenetics Morphological Gestational type A study by Matsuda et al. suggested that chromosome 7 contained a putative tumor suppressor gene for choriocarcinoma. Furthermore, by using a panel of microsatellite markers located on chromosome 7, they identified the critical region on chromosome 7 (7p12-7q11.23) which was biallelically deleted in choriocarcinomas. Another study by Ahmed et al., using the comparative genomic hybridization
technique, demonstrated amplification of 7q21-q31 and loss of 8p12-p21 in choriocarcinomas which did not occur in hydatidiform moles.
Genes involved and proteins Note Gestational type In the tumor suppressor genes, p53 (located on chromosome 17 and encodes for a 53 kDa nuclear phosphoprotein that binds to DNA and inhibits the progression of the cell cycle from G1 to S phase), the p21WAF1/CIP1 (a downstream effector of p53 and mediates growth arrest by inhibiting the G1 cyclin-dependent kinase), the retinoblastoma (Rb) gene (a reaction to the inactivation of Rb protein by forming a complex with over-expressed mdm2 proteins) were upregulated in choriocarcinoma than in normal placenta, and the DOC-2/hDab2 gene was downregulated. In oncogenes, the expression of c-myc, c-erb-B-2, c-fms and bcl-2 oncoproteins were studied in normal placenta, partial and complete moles, and choriocarcinoma. The study suggested that synergistic up-regulation of c-myc, c-erb-B-2, c-fms and bcl-2 oncoproteins may be important in the pathogenesis of complete mole and choriocarcinoma.
References Wake N, Tanaka K, Chapman V, Matsui S, Sandberg AA. Chromosome and cellular origin of choriocarcinoma. Cancer Res. 1981 Aug;41(8):3137-43
Buckley JD. The epidemiology of molar pregnancy and choriocarcinoma. Clin Obstet Gynecol. 1984 Mar;27(1):153-9
Sheppard DM, Fisher RA, Lawler SD. Karyotypic analysis and chromosome polymorphisms in four choriocarcinoma cell lines. Cancer Genet Cytogenet. 1985 Apr 1;16(3):251-8
. Gestational Trophoblastic Disease. Edited by Szulman AE, Buchsbaum HJ; 1987. Springer-Verlag. New York Inc.
Fisher RA, Newlands ES, Jeffreys AJ, Boxer GM, Begent RH, Rustin GJ, Bagshawe KD. Gestational and nongestational trophoblastic tumors distinguished by DNA analysis. Cancer. 1992 Feb 1;69(3):839-45
Arima T, Imamura T, Sakuragi N, Higashi M, Kamura T, Fujimoto S, Nakano H, Wake N. Malignant trophoblastic neoplasms with different modes of origin. Cancer Genet Cytogenet. 1995 Nov;85(1):5-15
Lorigan PC, Grierson AJ, Goepel JR, Coleman RE, Goyns MH. Gestational choriocarcinoma of the ovary diagnosed by analysis of tumour DNA. Cancer Lett. 1996 Jun 24;104(1):27-30
Suryanarayan K, O'Hanlan KA, Surti U, Ishwad CS, Nowels K, Letourneau D, Marina N. Nongestational choriocarcinoma in the postpartum period: a case report. J Pediatr Hematol Oncol. 1998 Mar-Apr;20(2):169-73
Ahmed MN, Kim K, Haddad B, Berchuck A, Qumsiyeh MB. Comparative genomic hybridization studies in hydatidiform moles and choriocarcinoma: amplification of 7q21-q31 and loss of 8p12-p21 in choriocarcinoma. Cancer Genet Cytogenet. 2000 Jan 1;116(1):10-5
Inaba H, Kawasaki H, Hamazaki M, Okugawa T, Uchida K, Honzumi M, Komada Y, Ito M, Toyoda N, Sakurai M. A case of metastatic ovarian non-gestational choriocarcinoma: successful treatment with conservative type surgery and myeloablative chemotherapy. Pediatr Int. 2000 Aug;42(4):383-5
Matsui H, Suzuka K, Iitsuka Y, Seki K, Sekiya S. Combination chemotherapy with methotrexate, etoposide, and actinomycin D for high-risk gestational trophoblastic tumors. Gynecol Oncol. 2000 Jul;78(1):28-31
Shigematsu T, Kamura T, Arima T, Wake N, Nakano H. DNA polymorphism analysis of a pure non-gestational choriocarcinoma of the ovary: case report. Eur J Gynaecol Oncol. 2000;21(2):153-4
Goswami D, Sharma K, Zutshi V, Tempe A, Nigam S. Nongestational pure ovarian choriocarcinoma with contralateral teratoma. Gynecol Oncol. 2001 Feb;80(2):262-6
Matsuda T, Wake N. Genetics and molecular markers in gestational trophoblastic disease with special reference to their clinical application. Best Pract Res Clin Obstet Gynaecol. 2003 Dec;17(6):827-36
Tsujioka H, Hamada H, Miyakawa T, Hachisuga T, Kawarabayashi T. A pure nongestational choriocarcinoma of the ovary diagnosed with DNA polymorphism analysis. Gynecol Oncol. 2003 Jun;89(3):540-2
Goto S, Ino K, Mitsui T, Kikkawa F, Suzuki T, Nomura S, Mizutani S. Survival rates of patients with choriocarcinoma treated with chemotherapy without hysterectomy: effects of anticancer agents on subsequent births. Gynecol Oncol. 2004 May;93(2):529-35
Lu KH, Gershenson DM. Update on the management of ovarian germ cell tumors. J Reprod Med. 2005 Jun;50(6):417-25
Yamamoto E, Ino K, Yamamoto T, Sumigama S, Nawa A, Nomura S, Kikkawa F. A pure nongestational choriocarcinoma of the ovary diagnosed with short tandem repeat analysis: case report and review of the literature. Int J Gynecol Cancer. 2007 Jan-Feb;17(1):254-8
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Multiple self-healing squamous epithelioma David R Goudie, Mariella D'Alessandro
East of Scotland Regional Genetics Service, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK (DRG), Cancer Research UK Cell Structure Research Group, Dundee University School of Life Sciences, MSI/WTB Complex, Dow Street, Dundee DD1 5EH, UK (MDA)
Published in Atlas Database: September 2008
Online updated version : http://AtlasGeneticsOncology.org/Kprones/MultSelfSquamEpithID10041.html DOI: 10.4267/2042/44572
Note Multiple self-healing squamous epithelioma is characterized by the development of multiple invasive skin tumours with the histological appearances of well differentiated squamous cell carcinomas that resolve spontaneously if left untreated leaving deep pitted scars.
Inheritance Autosomal dominant. Prevalence is unknown but over 100 cases have been reported worldwide with the majority of reported cases originating in Scotland.
Clinics Phenotype and clinics The age of onset of a first tumour is variable ranging from 8 to 62 years. Further tumours appear episodically throughout life with over a 100 tumours occurring in some more severely affected individuals. Tumours most commonly occur on areas of skin exposed to sunlight (the face, ears and limbs). Lesions are typically painless. They first appear as red papules and progress to nodules, often with a central keratin plug. Over time the lesions may ulcerate; when ulceration occurs, the edges are typically rolled and undermined.
Fig 1. Multiple lesions develop on sun-exposed areas of the body of patients, and all show spontaneous regression.
Multiple self-healing squamous epithelioma Goudie DR, D'Alessandro M
Fig 2. Histological section from a typical lesion. In this lesion, the collarette of epidermis on either edge and the eosinophilic cytoplasm, typical of a keratoacanthoma, are absent. (H&E; Scale bar: 100µm). Characteristically these tumours undergo spontaneous regression within 4-6 months, resulting in scars that are typically deep and pitted on the face, scalp and ears. Scars occurring on the limbs tends to be smoother and shallower. The tumours typically lack the collarette of epidermis on either edge and distinctive eosinophilic cytoplasm commonly observed in keratoacanthomas.
Neoplastic risk An increased risk of neoplasia at other sites has not been reported. The skin tumours invade locally and may be destructive but do not appear to recur following excision. Aggressive local invasion after radiotherapy has been described.
Treatment Surgical excision of tumours and cryotherapy of early lesions have been the most widely employed treatments. Etretinate was found to reduce the number of new lesions occurring in some patients.
Prognosis Scarring following tumour resolution can be disfiguring. Although tumours can be locally invasive most resolve spontaneously and metastases are very rare.
Genes involved and proteins Note The locus has been mapped to a 4Mb region of chromosome 9q22.3 in studies of affected families but the genetic defect causing the condition has not been identified. Loss of heterozygosity for 9q22.3 markers in self-healing epitheliomas is consistent with a tumour suppressor function for the MSSE locus.
Location 9q22.3
References Ferguson-Smith J.. A case of multiple primary squamous-celled carcinomata in a young man, with spontaneous healing. Br J Dermatol 1934;46: 267.
Wright AL, Gawkrodger DJ, Branford WA, McLaren K, Hunter JA. Self-healing epitheliomata of Ferguson-Smith: cytogenetic and histological studies, and the therapeutic effect of etretinate. Dermatologica. 1988;176(1):22-8
Goudie DR, Yuille MA, Leversha MA, Furlong RA, Carter NP, Lush MJ, Affara NA, Ferguson-Smith MA. Multiple self-healing squamous epitheliomata (ESS1) mapped to chromosome 9q22-q31 in families with common ancestry. Nat Genet. 1993 Feb;3(2):165-9
Chakrabarty KH, Perks AG. Ferguson-Smith syndrome: the importance of long term follow-up. Br J Plast Surg. 1996 Oct;49(7):497-8
Richards FM, Goudie DR, Cooper WN, Jene Q, Barroso I, Wicking C, Wainwright BJ, Ferguson-Smith MA. Mapping the multiple self-healing squamous epithelioma (MSSE) gene and investigation of xeroderma pigmentosum group A (XPA) and PATCHED (PTCH) as candidate genes. Hum Genet. 1997 Dec;101(3):317-22
D'Alessandro M, Coats SE, Morley SM, Mackintosh L, Tessari G, Turco A, Gerdes AM, Pichert G, Whittaker S, Brandrup F, Broesby-Olsen S, Gomez-Lira M, Girolomoni G, Maize JC, Feldman RJ, Kato N, Koga Y, Ferguson-Smith MA, Goudie DR, Lane EB. Multiple self-healing squamous epithelioma in different ethnic groups: more than a founder mutation disorder? J Invest Dermatol. 2007 Oct;127(10):2336-44
Identity Note The Silver Russell syndrome is characterized by intrauterine and postnatal growth retardation, craniofacial abnormalities, body asymmetry and delayed bone maturation.
Inheritance Most of patients with Silver Russell syndrome are sporadic, although autosomal recessive, autosomal dominant and X-linked dominant modes of inheritance have all been suggested.
Etiology The Silver Russell syndrome is genetically heterogeneous. Maternal uniparental disomy of chromosome 7 is observed in 7-10% of patients (7p11.2-p13 and 7q31-qter regions). More than 35% of patients carry a hypomethylation of the telomeric imprinting centre region 1 (ICR1) in 11p15 including the H19 and IGF-II genes; single patients show a maternal duplication of 11p15. Rare chromosomal rearrangements were found in the Silver Russell like syndrome involving the short arm of chromosome 7, the short and long arm chromosome 17 and the long arm chromosome 1.
Clinics Phenotype and clinics Abnormalities Growth : intrauterine growth retardation, short stature/dwarfism, poor postnatal growth below or lower than 2DS at diagnosis, delayed skeletal maturation during infancy. Craniofacial: Preservation of occipito-frontal head circumference, triangular face with prominent forehead, low-set ears, downturned mouth (fig.1).
Fig1 : The patient with Silver Russell syndrome: growth retardation, craniofacial abnormalities, preservation of occipito-frontal head circumference, triangular face and body asymmetry.
Differential Diagnosis It is a clinical overlap with other syndromes associated with intrauterine growth retardation and craniofacial abnormalities (Table 1).
Evolution Multidisciplinary management (pediatric, endocrinologic care etc.) is necessary. Growth hormone does not allow the target height to be reached.
Prognosis Beyond short stature and slender build, long-term prognosis is good.
References Moseley JE, Moloshok RE, Freiberger RH. The Silver syndrome: congenital asymmetry, short stature and variations in sexual development. Roentgen features. Am J Roentgenol Radium Ther Nucl Med. 1966 May;97(1):74-81
Gareis FJ, Smith DW, Summitt RL. The Russell-Silver syndrome without asymmetry. J Pediatr. 1971 Nov;79(5):775-81
Weiss GR, Garnick MB. Testicular cancer in a Russell-Silver dwarf. J Urol. 1981 Dec;126(6):836-7
Herman TE, Crawford JD, Cleveland RH, Kushner DC. Hand radiographs in Russell-Silver syndrome. Pediatrics. 1987 May;79(5):743-4
Chitayat D, Friedman JM, Anderson L, Dimmick JE. Hepatocellular carcinoma in a child with familial Russell-Silver syndrome. Am J Med Genet. 1988 Dec;31(4):909-14
Lai KY, Skuse D, Stanhope R, Hindmarsh P. Cognitive abilities associated with the Silver-Russell syndrome. Arch Dis Child. 1994 Dec;71(6):490-6
Al-Fifi S, Teebi AS, Shevell M. Autosomal dominant Russell-Silver syndrome. Am J Med Genet. 1996 Jan 2;61(1):96-7
Eggermann T, Wollmann HA, Kuner R, Eggermann K, Enders H, Kaiser P, Ranke MB. Molecular studies in 37 Silver-Russell syndrome patients: frequency and etiology of uniparental disomy. Hum Genet. 1997 Sep;100(3-4):415-9
Preece MA, Price SM, Davies V, Clough L, Stanier P, Trembath RC, Moore GE. Maternal uniparental disomy 7 in Silver-Russell syndrome. J Med Genet. 1997 Jan;34(1):6-9
Bernard LE, Peñaherrera MS, Van Allen MI, Wang MS, Yong SL, Gareis F, Langlois S, Robinson WP. Clinical and molecular findings in two patients with russell-silver syndrome and UPD7: comparison with non-UPD7 cases. Am J Med Genet. 1999 Nov 26;87(3):230-6
Price SM, Stanhope R, Garrett C, Preece MA, Trembath RC. The spectrum of Silver-Russell syndrome: a clinical and molecular genetic study and new diagnostic criteria. J Med Genet. 1999 Nov;36(11):837-42
Monk D, Wakeling EL, Proud V, Hitchins M, Abu-Amero SN, Stanier P, Preece MA, Moore GE. Duplication of 7p11.2-p13, including GRB10, in Silver-Russell syndrome. Am J Hum Genet. 2000 Jan;66(1):36-46
Hitchins MP, Stanier P, Preece MA, Moore GE. Silver-Russell syndrome: a dissection of the genetic aetiology and candidate chromosomal regions. J Med Genet. 2001 Dec;38(12):810-9
Anderson J, Viskochil D, O'Gorman M, Gonzales C. Gastrointestinal complications of Russell-Silver syndrome: a pilot study. Am J Med Genet. 2002 Nov 15;113(1):15-9
Monk D, Bentley L, Hitchins M, Myler RA, Clayton-Smith J, Ismail S, Price SM, Preece MA, Stanier P, Moore GE. Chromosome 7p disruptions in Silver Russell syndrome:
delineating an imprinted candidate gene region. Hum Genet. 2002 Oct;111(4-5):376-87
Nakabayashi K, Fernandez BA, Teshima I, Shuman C, Proud VK, Curry CJ, Chitayat D, Grebe T, Ming J, Oshimura M, Meguro M, Mitsuya K, Deb-Rinker P, Herbrick JA, Weksberg R, Scherer SW. Molecular genetic studies of human chromosome 7 in Russell-Silver syndrome. Genomics. 2002 Feb;79(2):186-96
Moore MW, Dietz LG, Tirtorahardjo B, Cotter PD. A multiplex methylation PCR assay for identification of uniparental disomy of chromosome 7. Hum Mutat. 2003 Jun;21(6):645-8
Gicquel C, Rossignol S, Cabrol S, Houang M, Steunou V, Barbu V, Danton F, Thibaud N, Le Merrer M, Burglen L, Bertrand AM, Netchine I, Le Bouc Y. Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nat Genet. 2005 Sep;37(9):1003-7
Bliek J, Terhal P, van den Bogaard MJ, Maas S, Hamel B, Salieb-Beugelaar G, Simon M, Letteboer T, van der Smagt J, Kroes H, Mannens M. Hypomethylation of the H19 gene causes not only Silver-Russell syndrome (SRS) but also isolated asymmetry or an SRS-like phenotype. Am J Hum Genet. 2006 Apr;78(4):604-14
Eggermann T, Schönherr N, Meyer E, Obermann C, Mavany M, Eggermann K, Ranke MB, Wollmann HA. Epigenetic mutations in 11p15 in Silver-Russell syndrome are restricted to the telomeric imprinting domain. J Med Genet. 2006 Jul;43(7):615-6
Netchine I, Rossignol S, Dufourg MN, Azzi S, Rousseau A, Perin L, Houang M, Steunou V, Esteva B, Thibaud N, Demay MC, Danton F, Petriczko E, Bertrand AM, Heinrichs C, Carel JC, Loeuille GA, Pinto G, Jacquemont ML, Gicquel C, Cabrol S, Le Bouc Y. 11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations. J Clin Endocrinol Metab. 2007 Aug;92(8):3148-54
Schönherr N, Meyer E, Roos A, Schmidt A, Wollmann HA, Eggermann T. The centromeric 11p15 imprinting centre is also involved in Silver-Russell syndrome. J Med Genet. 2007 Jan;44(1):59-63
Abu-Amero S, Monk D, Frost J, Preece M, Stanier P, Moore GE. The genetic aetiology of Silver-Russell syndrome. J Med Genet. 2008 Apr;45(4):193-9
Eggermann T, Meyer E, Caglayan AO, Dundar M, Schönherr N. ICR1 epimutations in llp15 are restricted to patients with Silver-Russell syndrome features. J Pediatr Endocrinol Metab. 2008 Jan;21(1):59-62
Fenton E, Refai D, See W, Rawluk DJ. Supratentorial juvenile pilocytic astrocytoma in a young adult with Silver-Russell syndrome. Br J Neurosurg. 2008 Dec;22(6):776-7
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This article should be referenced as such:
Piccione M, Corsello G. Silver Russell syndrome. Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9):688-690.
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Roles of tetraspanin proteins in cell and tumor biology Pedro A Lazo
Programa de Oncología Translacional, Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Salamanca, E-37007, Spain (PAL)
Published in Atlas Database: September 2008
Online updated version : http://AtlasGeneticsOncology.org/Deep/TetraspaninID20062.html DOI: 10.4267/2042/44574
Tetraspanin protein family and its web In the human proteome, there are thirty-three proteins composing the tetraspanin (Tspan) family, which are a group of highly hydrophobic membrane proteins defined by their structural characteristics (Figure 1). Tetraspanins have four transmembrane domains with short intra-cytosolic N- and C-terminal regions, and two extracellular (EC) loops (Tarrant et al., 2003). The large EC2 loop has
distinctive characteristics, such as a conserved CCG motif and conserved cysteines permitted the identification of a protein signature (Shoham et al., 2006), so that three tetraspanin subgroups are identified based on their folding patterns (Seigneuret et al., 2001). The hydrophobic transmembrane regions also contain conserved polar residues (Figure 1). The short C-terminal region is likely to provide a link to intracellular signaling molecules (Stipp et al., 2003). Tetraspanin biology should be considered as a compartmentalized system (Levy and Shoham, 2005).
Figure 1
Roles of tetraspanin proteins in cell and tumor biology Lazo PA
The tetraspanin web is a complex containing several tetraspanins interacting among themselves on the membrane, forming a core that can interact with many different molecules; thus the composition of individual complexes is very likely to determine different biological effects (Lazo, 2007), making it a compartmentalized system. Most of the knowledge on this web was obtained from a small number tetraspanins, mainly CD9, CD81, CD82 and CD151 (Hemler, 2005). CD53, CD63 and CD37 have also been detected in complexes, and the remaining tetraspanins have not been studied in this context. Their combination permits a large variability, forming platforms for associated proteins (Levy and Shoham, 2005), which is very
likely to be more important biologically than individual components. These proteins are expressed in most cell types (Wright et al., 2004), but most of the functional information has been obtained in cells of the hematopoietic system or epithelial cells (Hemler, 2005).
The tetraspanin partners in the web Individual tetraspanin proteins can interact with several different types of proteins (Levy and Shoham, 2005), most of which play a receptor role, or alternatively couple receptors to signalling pathways. These interacting proteins range from membrane receptors, adhesion molecules to signal transduction molecules (Table 1).
Roles of tetraspanin proteins in cell and tumor biology Lazo PA
Some of these protein-protein interactions are restricted to a specific tetraspanin protein. The combination of tetraspanins and the proteins listed in Table 1 suggests there are multiple different combinations between tetraspanins and their associated proteins. Although some combinations are specific, clearly many others remain to be identified. This heterogeneity of tetraspanin interactions with a variety of membrane proteins is likely to determine the biological role of tetraspanins as costimulatory molecules.
Interactions with integrins, relevance to cellular adhesion Individual interactions between tetraspanins and integrins but are the most extensively studied interaction, but their web context was not considered (Berditchevski, 2001). However, despite the relevance of integrins in processes such as adhesion to extracellular matrix, cell motility, invasion and angiogenesis (Janes and Watt, 2006; Watt, 2002), the functional consequences of these interactions have received relatively little attention, perhaps because no tetraspanin ligand has so far been identified. The main integrin found associated are those containing the β1 chain, mostly combined with α3, α4 or α6, in most cell types; and less frequently α2 and α5 (Berditchevski, 2001). The β1 chain is a major component of the attachment to the extracellular matrix (Hemler and Lobb, 1995), and signals by the activation of the integrin-linked kinase (ILK) (Dedhar, 2000). Some of these interactions have been reported for a specific tetraspanin, as is the case of α1β1 with CD9, but others as α4β1 were detected associated to CD9, CD53, CD81, CD82 or CD151. A direct interaction has only been demonstrated for CD151-α3β1 (Yauch et al., 2000). In general it can be concluded that one α integrin can bind to more than one type of tetraspanin. Although the β chain also contributes to the interaction, as exemplified by CD151 that interacts with α6β1 and α6β4 (Berditchevski et al., 1996). These CD151-integrin interactions strengthened the attachment to the extracellular matrix (Nishiuchi et al., 2005), but if they are functionally different depending on cell type, lymphoid or epithelial, is not known. The tetraspanin complex with integrins is in low affinity conformation, and changes in affinity do not alter the integrin-tetraspanin interaction and integrin activation does not affect their tetraspanin interaction (Berditchevski, 2001), but tetraspanins appear to affect the post-ligand effects such as modulating actin dynamics, reflected in migration and cell adhesion properties. The tetraspanin-integrin complexes a might provide spatial cues for cellular polarization (Yanez-Mo et al., 2001).
Growth factor receptors and other membrane receptors Growth factor receptors is a major group of Tspan
interacting proteins, the receptors belong to different types (Table 1) including those with immunoglobulin domains, particularly those of the EWI family, but without considering their supramolecular organization, which can affect the magnitude or specificity of their effects and the functional consequences of any of them are unknown. Regarding growth factor receptors with tyrosine-kinase activity, CD9 interacts with the HB-EGF receptor (Lagaudriere-Gesbert et al., 1997) and. c-Met/HGF-R (hepatocyte growth factor receptor), the receptor for the scatter factor (SF) or HGF that is implicated in epithelial-mesenchimal transition, a fundamental process in the dissemination of tumor cells (Trusolino and Comoglio, 2002) c-Met interacts with CD82 (Sridhar and Miranti, 2006). The interaction of the ganglioside GM2 with the CD82-c-Met inhibits its cross-talk with integrin signaling, and reduces c-Met activation signal (Todeschini et al., 2008). In epithelial cells CD9 interacts with epithelial cell adhesion molecule (Ep-CAM) (Le Naour et al., 2006). But the functional consequences of interactions between different tetraspanins and cadherins have not yet been performed. It can be concluded that our knowledge on tetraspanin effects on signals initiated in interacting growth factor receptors is rather limited.
Membrane proteins Proteins of the HLA family, both class II and class I, constitute a major group of proteins associated with tetraspanins (Lagaudriere-Gesbert et al., 1997; Szollosi et al., 1996).The most characterized is the interaction with class II antigens, but class I have also been detected (Berditchevski and Odintsova, 2007; Engering and Pieters, 2001; Szollosi et al., 1996), particularly with CD53, CD37 or CD81 (Angelisova et al., 1994). However, if tetraspanin proteins modulate signals or functions mediated by these HLA antigens has not been characterized, but are likely to affect antigen presentation (Berditchevski and Odintsova, 2007). In dendritic cells the lateral interaction between CD9 and MHC class II antigen facilitated T-cell activation (Unternaehrer et al., 2007). It will be important to determine their functional consequences in tumor cells were HLA antigens expression is frequently downregulated to facility immune evasion.
Intracellular signaling molecules Tetraspanins are considered as molecular facilitators because they participate, or modulate, several signaling and biological processes (Maecker et al., 1997), detected in very heterogeneous cell types, but their implication is clear; tetraspanins can influence intracellular signaling, directly or indirectly, and thus can modulate signals initiated in other membrane receptors that are present on the Tspan web. Due to the lack of any known ligand, most signals have been
Roles of tetraspanin proteins in cell and tumor biology Lazo PA
studied using specific monoclonal antibodies. In this regard CD9, CD82, CD81 and CD53 are the best-characterized antigens (Boucheix and Rubinstein, 2001). In this context CD9, CD82, CD81 and CD53 are the best-characterized antigens (Boucheix and Rubinstein, 2001). Among signals detected in response to tetraspanin antigen ligation by monoclonal antibodies were calcium mobilization by CD9, CD53, CD81 or CD82, protein kinase C activation, increased levels of diacylglycerol, activation of phosphatidylinositol 3-kinase (PI 3K) and phospholipase Cγ (Boucheix and Rubinstein, 2001). Another component of tetraspanin signaling is a consequence of direct physical interaction between some tetraspanins, such as CD151, and type II phosphatidylinositol 4-kinase (PI 4K); in this case the tetraspanin functions as the connector between the associated integrin and the PI 4K molecule (Berditchevski et al., 1997; Claas et al., 2001). Only some tetraspanins, CD9, CD63, CD81, A15 and CD151 are associated with PI 4K, but not others such as CD82, CD53 or CD37; and their interaction does not require previous binding to an integrin, therefore it may be mediated by a not yet identified protein, and will have functional consequences depending on the pattern of expression and integration in the tetraspanin web in different cell types. All these effects have been reported in very heterogeneous cell types. But the implication is clear; tetraspanins can influence intracellular signalling, directly or indirectly, and thus can modulate signals initiated in other membrane receptors. CD53 ligation activates protein kinase C (PKC) (Barcia et al., 1996; Bosca and Lazo, 1994; Lazo et al., 1997); and later it was demonstrated that following cell stimulation, PKC binds to the intracellular side of CD9, CD53, CD81, CD82, and CD151 (Zhang et al., 2001), this bound PKC was able to phosphorylate the integrin α3 subunit interacting with CD151. Also CD53 ligation could transiently activate the c-jun NH2-terminal kinase (JNK) and c-Jun dependent transcription (Yunta et al., 2002). In renal mesangial cells the ligation of CD53 induced a proliferative response mediated by the extracellular-regulated kinases, ERK1 and ERK2 (Yunta et al., 2003). Furthermore, CD53 and CD63 have been found associated with a tyrosine phosphatase (CD45) that dephosphorylates lck (Carmo and Wright, 1995).
The tetraspanin web is regulated by lipids:
Palmitoylation determines the formation of cholesterol rich microdomains Membrane proteins can be covalently modified by palmitoylation that can control their association and organization in different cellular membranes. The tetraspanins CD9, CD37, CD53, CD63, CD81, CD82 and CD151 are palmitoylated molecules (Charrin et al., 2002), that occurs in intracellular cysteines; and which is a requirement for their association with cholesterol complexes (Charrin et al., 2003). The assembly of the tetraspanin web is started in the Golgi, where homodimers, as well as heterodimers, of CD9, CD81, or CD151, constituting intermediate building blocks in the assembly of the tetraspanin web (Kovalenko et al., 2004). Palmitoylated tetraspanins appeared to be important for assembly of the web, favoring association with other tetraspanins and their associated proteins (Berditchevski et al., 2002; Yang et al., 2002). Palmitoylated CD9, CD81, and CD63 colocalize with palmitoylated integrin beta4, which promoted the incorporation of CD151 to these tetraspanin complexes (Yang et al., 2004). There are two types of complexes, those with palmitoylated tetraspanins that facilitate their association with integrins and integration in cholesterol-rich fractions, and those non-palmitoylated tetraspanins that are accessible to binding with different signaling molecules, such as 14-3-3, p130 (CAS) or EWI proteins among others. These two alternative signaling complexes are summarized in Fig.2. Palmitoylation of CD9 promotes interaction with integrins and association with other tetraspanins, CD81 and CD53. Mutations in all palmitoylation residues CD9 (Charrin et al., 2002) or CD151 (Yang et al., 2002) resulted in a more diffuse distribution and prevented their association with cholesterol. Un-palmitoylated CD9 is freer and has an enhanced binding to EWI-2 and EWI-F (Yang et al., 2006). The loss of palmitoylation did not affect spreading on extracellular matrix, but these cells have a larger number of focal adhesions, and an increase in adhesion-induced phosphorylation of Akt, without affecting activation of FAK or ERK1/2 (Berditchevski et al., 2002). Palmitoylation also controls the association between tetraspanins and intracellular signaling molecules. In these complexes, tetraspanin ligation increased phosphorylation of signaling molecules such as vav, and effect lost by treatment with cholesterol disrupting detergents (Charrin et al., 2003).
Roles of tetraspanin proteins in cell and tumor biology Lazo PA
In B-cells the coligation of the B-cell receptor (BCR) with CD19/CD21/CD81 promoted CD81 palmitoylation and stabilization of the complex within a cholesterol rich fraction (Cherukuri et al., 2004). CD82 palmitoylation is necessary for mobility and invasion of PC13 cells, and loss of palmitoylation resulted in abolishment of these properties, and in regaining interaction with the p130 (CAS)-CrkII signaling complex (Zhou et al., 2004), also detected in CD9 (Yang et al., 2004). Palmitoylation was regulated by the cellular redox state, and under oxidative stress palmitoylation is inhibited favoring signaling by 14-3-3 adaptor proteins (Clark et al., 2004), thus not palmitoylated CD81 was constitutively bound to 14-3-3 protein, a serine/threonine binding protein (Clark et al., 2004).
Gangliosides can regulate the composition of the tetraspanin web Gangliosides are complex glycolipids which contain a branched chain of as many as seven sugar residues. Several specific interactions of gangliosides with tetraspanins have been reported. Thus GM3 ganglioside preferentially interacts with CD9 (Kawakami et al., 2002; Mitsuzuka et al., 2005) and CD81 (Toledo et al., 2004), reducing MAPK activation initiated in FGFR (Toledo et al., 2004). GM3, promotes the association of CD9 with the α3 integrin (Kawakami et al., 2002) or &alpha5; inhibiting cell motility (Miura et al., 2004). The GM2 ganglioside is mainly associated with CD82 (Odintsova et al., 2006; Todeschini et al., 2008), and
GD2/GD3 gangliosides interacting with CD151 (Thorne et al., 2007) and CD82 inhibited cell motility (Todeschini et al., 2008).
Dynamics of tetraspanin microdomains: cell-specific complexes The web assembly of tetraspanins and their specific interactions can be interpreted within the general framework of the dynamics of a complex with the potential for a very high functional heterogeneity (Fig.2). In this system there is a double level to increase complexity, the participation of the tetraspanins in the core, and the type and number of associated proteins. Thus diversity in the combination of proteins permits a very large flexibility which can determine functional differences depending on cell type. Therefore, tetraspanin complexes in specific cell types can be very different despite sharing several of their components. In that way the association of tetraspanin-membrane receptor may exist either as isolated complexes on cell surfaces, or forming part of a larger tetraspanin-core complex. Thus, the association-dissociation kinetics represents an important level of regulation, where palmitoylation and redox state play a major role, but these properties have not yet been characterized in detail in any system. Initiation of cell signals is very likely to be different if activated by either free molecules, in heterodimers, or a larger complex, such as the tetraspanin web.
Roles of tetraspanin proteins in cell and tumor biology Lazo PA
Contribution of Tetraspanins to tumor biology: cell adhesion and motility: CD151. CD151 is mainly localized to the basal and lateral junctions of endothelial cells (Berditchevski and Odintsova, 1999) and blocking antibodies increased their adhesion to the ECM and reduced their rate of invasion in collagen gels (Yanez-Mo et al., 1998). In migrating ketarinocytes and breast cancer cells CD9, CD81, CD151 were involved in transient interactions with the substrate before a more stable interaction could be formed by attachment structures due to lamellopodia formation (Penas et al., 2000). These structures were both did not contain elements of the cytoskeleton, and colocalized with MARCKS, which are substrates of PKC that regulates cytoskeleton reorganization during migration (Berditchevski and Odintsova, 1999). In human skin, CD151 was clustered at the basal cell colocalizing with laminin 5 (Lagaudriere-Gesbert et al., 1997; Yamada et al., 2008) connecting focal adhesion with actin filaments as part of hemidesmosomes (Sterk et al., 2000). In polarized epithelial cells, CD9, CD151 and CD81 also localize with cadherins at lateral cell-cell contacts although the effect of antibodies is cadherin-independent. Overexpression of CD151 resulted in increased motility, and enhanced expression of matrix metalloproteinase-9 (MMP-9) and invasiveness (Hong et al., 2006); probably as a result of activating pathways mediated by small GTPases (Shigeta et al., 2003). CD151 knock-down in primary melanocytes resulted in a loss of motility (Garcia-Lopez et al., 2005), effects that are reversed by CD151 reexpression (Winterwood et al., 2006). The dissociation of CD151 from laminin-binding integrins permitted migration of epithelial cells (Chometon et al., 2006).These data on signaling and motility clearly implicate CD151 in cell adhesion and dissemination. The blocking of CD151 with an antibody is able to prevent tumor intravasation and metastasis (Zijlstra et al., 2008).
CD82. CD82 functions as a link between the actin cytoskeleton and membrane raft domains, inducing stable adhesion, spreading and development of membrane extensions. CD82 effects on actin polymerization depend on its association with the ECM and involves src kinases, Vav1, and p56 lck (Delaguillaumie et al., 2002; Lagaudriere-Gesbert et al., 1998). The depletion of gangliosides also destabilizes CD82 complexes (Ono et al., 1999), reducing interaction with CD151 and increasing the interaction with EGFR (Odintsova et al., 2006) and c-Met (Todeschini et al., 2007). All these effects are severely affected by cholesterol depletion (Delaguillaumie et al., 2004).Overexpression of CD82 might contribute to tumor invasion by inhibiting the cross-talk between integrins and Met and src activation
and phosphorylation of its downstream targets, p130Cas and FAK (Sridhar and Miranti, 2006; Zhang et al., 2003). Inhibition of c-Met or Src reduced invasion to the same extent as CD82 e(Sridhar and Miranti, 2006). High levels of CD82 correlate with a lower invasion potential in prostate (Zhang et al., 2003), lung (Adachi et al., 1996), esophageal cancer (Uchida et al., 1999) and by its overexpression in multiple myeloma cell lines (Tohami et al., 2007). CD82 surface expression is up-regulated by several cytokines such as interleukin-1 beta (IL-1 beta), IL-4, IL-6 , IL-13, interferon-gamma, tumor necrosis factor-a antigen (Lebel-Binay et al., 1995b). Co-ligation of CD82 and Fc receptors induces an increase in calcium level mediated by phospholipase C (PLC)-induced PtdIns(1,4,5)P3 second messenger followed by a more stable change, linked to extracellular calcium entry (Lebel-Binay et al., 1995b). In Jurkat cells stimulated of with anti-CD82 and anti-CD3 mAbs implicates different transcription factors such as NF-AT, AP-1, and NF-κB (Iwata et al., 2002), with increased production of IL-2; and cells become adherent developing dendritic extensions, cell proliferation is arrested (Lebel-Binay et al., 1995a). The interaction of Cd82 with DARC (duffy antigen receptor for chemokines) a in on prostate and endothelial cells has been identified as a binding partner of CD82 cells (Bandyopadhyay et al., 2006), makes them to enter senescence (Iiizumi et al., 2007).
CD9. The association of CD9 with the transmembrane region of TGF-α resulted in the induction of EGFR activation and cellular proliferation (Shi et al., 2000). Also, the metalloprotease ADAM10 promotes the association of CD9 with HG-EGF (Yan et al., 2002). But CD9 has been associated with control of cell motility. Functionally antibodies anti-CD9 inhibited transmigration of melanoma cells (Longo et al., 2001). In primary melanocytes where reduction of CD9 by siRNA resulted in loss of motility (Garcia-Lopez et al., 2005). Cell motility dependent on binding to laminin-5 is inhibited by the interaction of CD9 with the GM3 ganglioside (Kawakami et al., 2002). All these data suggested that CD9 as well as CD81 loss are likely to promote tumor dissemination. In agreement with this potential role, an inverse correlation between CD9 level and invasiveness has been reported in melanomas (Si and Hersey, 1993), breast cancer (Huang et al., 1998), oral squamous cell carcinomas (Kusukawa et al., 2001), ovarian carcinoma (Houle et al., 2002), and cervical carcinomas (Sauer et al., 2003b).
CD81. The ligation of CD81 initially had an antiproliferative effect, and regulated the intracellular thiol levels (Schick et al., 1993), forming part of the CD19/CD21 signaling complex on B-cells (Behr and Schriever, 1995). CD81 and CD151 tetraspanin molecules are components of the endothelial lateral
Roles of tetraspanin proteins in cell and tumor biology Lazo PA
junctions implicated in the regulation of cell motility, either directly or by modulation of the function of the associated integrin heterodimers (Yanez-Mo et al., 1998); and CD81 was associated with adhesion and motility in lymphocytes (Levy et al., 1998). The link between CD81 and the actin cytoskeleton seems to be mediated by EWI-2 and EWI-F (Sala-Valdes et al., 2006). CD81 overexpression reduces viability and motility in multiple myeloma cell lines (Tohami et al., 2007).
CD63. CD63 antigen is mostly detected at a very high concentration in endosomal particles; but it is also presented on cell surfaces. The C-terminal intracellular region of CD63 interacts with the PDZ domain of syntenin-1, a molecule that is implicated in regulation of endocytosis and slows down CD63 internalization (Latysheva et al., 2006). CD63 expression on cell surface affects tumor dissemination. The loss of CD63 was the first tetraspanin to be related with a very high invasive potential in melanomas, where an inverse correlation between CD63 levels and metastatic potential was identified (Hotta et al., 1988; Hotta et al., 1989), and its reexpression in melanoma cells reduced its invasion potential (Radford et al., 1995). A similar correlation has been reported in a colon carcinoma cell line (Sordat et al., 2002).
CD53: Radioresistance and effects on redox state The CD53 ligation antigen with specific antibodies stimulates several processes such as the induction of nitric oxide synthase (Bosca and Lazo, 1994) in macrophages, homotypic cell adhesion in B-cell lymphomas (Lazo et al., 1997), or DNA synthesis in mesangial cells (Yunta et al., 2003), all of them on PKC activation. Part of the signal is also transmitted by the JNK system and has a protective effect on apoptosis in Jurkat cells (Yunta and Lazo, 2003). CD53, CD82 and CD81 interact with gamma-glutamyl transpeptidase (GGT) a regulator of the intracellular redox state by modulating level of glutathione (Nichols et al., 1998). This is a very interestingly observation because the mechanism by which cells are killed by radiation therapy is based on its ability to generate free radicals in the cell; and is therefore strongly dependent on the intracellular redox state. Very high overexpression of CD53 is one of the main markers of radioresistant cells (Voehringer et al., 2000), resulting in an increase in the intracellular level of glutathione, which has anti oxidant properties and thus counteracts the radiation effect facilitating cell survival (Voehringer et al., 2000).
Patterns of tetraspanin protein expression in normal and stem cells:
Tetraspanin surface expression in hematopoietic cells The only overall picture of tetraspanin surface expression has been obtained in human B-cell maturation, in which the relative surface levels of six tetraspanins (CD9, CD37, CD53, CD63 and CD81), and their interacting proteins (CD19, CD21, and HLA-DR) was determined (Barrena et al., 2005b). This study identified three different combinations based on developmental stage: I) early bone marrow (BM) CD10+ B-cell precursors have high levels of CD81 and CD9 and relatively very low level of CD53, and negativity for CD37; II) mature/peripheral B-lymphocytes (CD10-) there is down-regulation of CD9/CD81 and up-regulation of CD53/CD37; III) in plasma cells that have passed through secondary lymphoid tissues and reentered the BM there is CD9 re-expression and CD37 down-regulation, but maintain the CD53 expression. These distinct patterns of tetraspanin expression may reflect the occurrence of different cellular interactions and homing properties during B-cell maturation. (Barrena et al., 2005b). Although precursors of lymphoid cells express relatively higher levels of CD9, they also express CD53 and CD63 intracellularly located in endosomes, two proteins that in CD133+ stem cell population are distributed asymmetrically (Beckmann et al., 2007), a hallmark of stem cells, but its significance is unknown.
Tetraspanin proteins in epithelial cells A systematic approach to detect six tetraspanin proteins, CD9, CD37, CD53, CD63, CD81, and CD82, in the gastrointestinal (GI) tract has been performed. Two of them, CD9 and CD82 were expressed at similarly high levels throughout the GI tract, from esophagus to colon. CD63 expression was more restricted, ranging from distal stomach to colon. CD81 was detected only in basal layers of the esophagus. CD53 was barely detected and no expression of CD37 was observed (Okochi et al., 1999). These differences suggest that the organization of the tetraspanin web can present major variations depending on its localization in the GI; but their functional significance is not known. Tetraspanin proteins have also been used to attempt to identify epithelial precursor cells in the airway tract, which is severely damaged in diseases such as cystic fibrosis. In the basal cells of the trachea there is compartment of stem and transit amplifying cells. A marker of early stages is the detection of CD151 in combination with TF (Tissue factor) antigens. Therefore, tracheal cells positive for CD151/TF were able to proliferate and reconstitute a fully differentiated
Roles of tetraspanin proteins in cell and tumor biology Lazo PA
epithelium in rat with epithelium-denuded trachea. These cells were also positive for telomerase activity, which is considered a marker for the transit amplifying population. Cells of the columnar epithelium, CD151/TF negative were unable to proliferate or reconstitute the epithelium and have no telomerase activity. These data suggest that adult basal cells, CD151 positive, are present in the amplification compartment of the epithelium and have some regenerative potential (Hajj et al., 2006). It is not known if in other epithelial cells the situation is similar. In the basal layer of normal squamous cervical epithelium there is a very high expression of CD9; which is down-regulated in squamous cervical carcinomas correlating with stage, but surprisingly as the tumor progresses there is a re-expression of CD9 as it becomes more vascularized, what might be an important element to permit tumor dissemination (Sauer et al., 2003b), and might reflect an interaction with vascular cells not yet identified.
Tetraspanins in human cancer Most the information on expression of multiple tetraspanin proteins is a consequence of the information obtained using expression microarray in the analysis of different types of human cancer. These studies provide information on two aspects, the antigens expressed based on a given phenotype, and the relative change in the pattern as a function of differentiation or tumor phenotype, which indicate that they are functionally different.
Tetraspanin proteins in B-cell malignancies The cell surface expression of four tetraspanin antigens and associated proteins has been studied in sixty-seven cases of B-cell malignancies (Barrena et al., 2005b). Hierarchical clustering analysis of flow cytometry immunophenotypic data showed a good correlation between the tumor differentiation stage and the pattern of tetraspanin expression (Barrena et al., 2005b). Mature/peripheral B-cell leukemias and lymphomas expressed high levels of CD37 and CD53; while those derived from BCP-ALL (acute lymphocytic leukemia), and clonal plasma cells (PC) coexpressed CD9 with either CD81 or CD53, respectively. Despite these phenotypic similarities, variable levels of expression of one or more of these proteins were frequently expressed and of these phenotypic aberrations were common to most patients within a specific disease group. The differences in the pattern of tetraspanin surface expression can be used to discriminate two different lymphomas in an individual patient (Barrena et al., 2005a). In B-CLL, the pattern of expression of CD9 and CD53 tetraspanins was associated with the pattern of in vivo tissue involvement. Thus, abnormally high reactivity for CD53 was associated with greater
PB and lymph node infiltration. Previously it was demonstrated that ligation of CD53 antigen protects lymphoid cells from apoptosis (Yunta and Lazo, 2003), an important property for mature/peripheral memory lymphocytes. Therefore, overexpression of CD53 could render B-CLL (chronic lymphocytic leukemia) cells more adapted to survive in peripheral blood (PB) and lymph nodes. In contrast, reduced CD9 expression on B-CLL cells has been associated to a higher bone marrow (BM) involvement. CD9 also functions as a motility/migration brake (Ono et al., 1999), and this might explain the correlation detected between CD9 expression and the pattern of BM involvement. In multiple myelomas (MM), there is CD9 expression in non active MM, while in active and aggressive MM there is an epigenetic silencing of CD9 gene expression (De Bruyne et al., 2008).
Tetraspanin proteins in carcinomas Information on expression in carcinomas is derived mostly or from gene expression arrays and from determining few protein antigens; and functional information has been obtained from tumor cell lines. Tetraspanins have received little attention in human carcinomas but some information is emerging form three different lines of work. The alternative expression of some tetraspanin antigens permits the identification of subgroups in different types of human cancer. The coordinated expression of tetraspanin initially identified in B-cells (previous section) appears to be more general. In kidney cancer, high expression of CD53 and CD37 inversely correlated with respect to CD9 expression (low) in conventional renal cell carcinomas of clear cells and in papillary carcinomas, but not in other types such as granular carcinomas in which CD9 expression is very high (Higgins et al., 2003). Also, in melanomas there is no CD53 and CD37 expression and express varying levels of CD9, the latter is inversely correlated with metastatic potential (Si and Hersey, 1993), a pattern consistent with a higher probability of infiltration in lymph nodes (Barrena et al., 2005b). The loss of CD9 antigen has been correlated with higher motility and metastatic potential of tumor cells from lung (Higashiyama et al., 1995), esophageal (Uchida et al., 1999), oral (Kusukawa et al., 2001), ovarian (Houle et al., 2002), cervical (Sauer et al., 2003b), gastric (Hori et al., 2004) carcinomas. In the basal layer of the normal squamous epithelium of the uterine cervix CD9 is strongly expressed, but in invasive carcinomas is downregulated. However in some areas there is a re-expression of CD9 that were correlated with lymphangiosis. This cluster of CD9 might be an indicator of a higher risk of recurrence, since CD9 plays a role in transendothelial migration (Sauer et al., 2003b). In bladder cancer cell lines GM3 in glycosynapse 3 has a dual functional role. The first
Roles of tetraspanin proteins in cell and tumor biology Lazo PA
one modulates the interaction between α3 integrin and CD9; the second is to activate or inhibit the activity of c-src. Functionally high levels of GM3 reduce motility and invasiveness, while low levels have the opposite effect (Mitsuzuka et al., 2005). In melanomas CD63, one of the original tetraspanins was identified in melanomas, where its levels inversely correlated with metastatic potential (Hotta et al., 1988), and in cell lines its overexpression suppresses the malignant phenotype (Hotta et al., 1991). The expression of four tetraspanin proteins, CD9, CD63, CD82 and CD151 was studied in breast carcinoma cell lines with different invasive capabilities in in vitro assays. The expression of three of them, CD9, CD63 and CD151 appeared to be coordinated by a common mechanism, and low levels clearly predicted their invasive potential, particularly for CD63 (Sauer et al., 2003a). Tetraspanin expression has been studied in a model of colon carcinoma with cell lines derived from primary tumors and two from metastasis. Thirty-two proteins were detected by a proteomic approach and included integrins, proteins with Ig domains, CD44, and epithelial cell adhesion molecule (EpCAM), membrane proteases (ADAM10, TADG-15, and CD26/dipeptidyl peptidase IV), and signaling proteins (heterotrimeric G proteins). Also some differences were identified, particularly the Co-029 tetraspanin antigen in the metastasis, that was almost absent in primary tumors, but very high in normal colon (Le Naour et al., 2006). In thyroid tumors CD82 is highly expressed in benign goiter, but expression was significantly reduced in carcinomas and were reduced even further in metastasis; in these tumors there were no changes in the expression of CD63 (Chen et al., 2004). Some prostate carcinomas have downregulated CD9 and CD53 in those cases with high levels of CD151; CD9 and CD53 are upregulated in another group of prostate carcinomas (Lapointe et al., 2004). In these tumors CD9 and CD53 expression seems to be positively coordinated, which is the opposite of what occurs has been detected in other cell types. In low-grade prostate cancer the survival rate was higher in those cases were CD151 levels were lower, and in this study CD151 had a better prediction value than histological (Gleason) grade (Ang et al., 2004). In murine prostate cancer cells can attach to vascular endothelial cells through DARC, and this interaction inhibits proliferation and induces senescence by expression of TBX2 and p21 (Bandyopadhyay et al., 2006). The role of CD82 as a metastasis suppressor is compromised in DARC knockout mice. All these data suggests that the interaction DARC-CD82 is essential for the metastasis suppressor role of CD82 (Bandyopadhyay et al., 2006). It would be interesting to know if a similar interaction is found for other tetraspanin proteins that also behave as metastasis suppressors.
Bladder cancer represents a particular tumor due to its mechanical properties. The expression of uroplakins, an antigen that seals the bladder epithelium, can be used to identify the type of tumors and its severity. Uroplakin II is mainly expressed in transitional bladder carcinomas but not in squamous cell carcinomas and can be use to monitor for circulating cancer cells and in metastasis (Olsburgh et al., 2003). In breast cancer CD151 is overexpressed in a third of the cases and correlates with high grade, and estrogen receptor negative tumors. The effect of CD151 is mediated by the upregulation of signals by integrin α6 through FAK, Rac1, and lck (Yang et al., 2008).
The future of tetraspanins in cancer biology Despite the very heterogeneous information on tetraspanin proteins in relation to cancer, it is very likely that patterns of expression of these proteins will affect the behavior of tumor cells with respect to signaling by growth factors, cell motility and sensitivity to therapy, which will be identified when these studies are performed. The regulatory role played by palmitoylation and gangliosides will require further characterization since they modulate cell signaling by associated growth factor receptors. It is expected that in the future these proteins will attract more attention and be studied in the proper context within tumor biology, since they are likely to play an important role in conferring specificity to many biological effects. Although the basic processes where tetraspanin proteins play a role have already been outlined, their specific participation in these processes and in different cell types will require a systems approach where the multiplicity of components, their relatives levels, and localization are taken simultaneously into account thus generating a specific cell behavior. Their systematic determination in specific tumors is very likely to predict, and/or identify, their metastatic potential.
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This article should be referenced as such:
Lazo PA. Roles of tetraspanin proteins in cell and tumor biology. Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9):691-703.
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