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Clear Cell Renal Cell Carcinoma and the Novel Tumor Suppressor SETD2
Histological subtypes of RCC show unique chromosomal abnormalities
Clear Cell RCC nodular growth with areas of hemorrhage and necrosis
3p deletions
Papillary RCC solid white mass
Trisomy 7 and 17, loss of Y
Chromophobe RCC
expansile mass with a solid yellow-brown cut surface
Loss of multiple chromosomes
1, 2, 6, 10,
ccRCC lines show lack of solid tumor hallmarks such as RAS, BRAF, TP53, PTEN and EGFR
Inactivation of the VHL is not sufficient to cause ccRCC in mice
ccRCC is characterized by LOH of chromosome 3
International Journal of CancerVolume 125, Issue 10, pages 2342-2348, 11 JUN 2009 DOI: 10.1002/ijc.24642http://onlinelibrary.wiley.com/doi/10.1002/ijc.24642/full#fig1
Histones organize DNA, regulate expression, and can be modified
During transcription, histones are transiently both modified and exchanged
SETD2 is a non-redundant H3K36-specific trimethyltransferase
SETD2 regulates cryptic transcription at internal exons
SETD2 is necessary for chromatin-remodeler FACT’s recruitment
Knockdown of SETD2 decreases H2B occupancy in internal exons
Loss of SETD2 affects vascular remodeling in mice
Changes in SETD2 alter global gene expression
References 1. Kleymenova, E. "Susceptibility to Vascular Neoplasms but No Increased Susceptibility to Renal Carcinogenesis in
Vhl Knockout Mice." Carcinogenesis 25.3 (2003): 309-15. 2. Duns, Gerben, Inge Van Duivenbode, Jan Osinga, Harrie Hollema, Eva Van Den Berg-De Ruiter, Robert M.W.
Hofstra, and Klaas Kok. "Histone Methyltransferase Gene SETD2, a Novel Tumor Suppressor Gene in Clear Cell Renal Cell Carcinoma."Cancer Genetics and Cytogenetics 203.1 (2010): 45.
3. Buning, Ruth, Wiepke Koopmans, Heinz Neumann, Jason Chin, and John Van Noort. "Regulation of Nucleosome Conformational Dynamics by Post-Translational Histone Modifications Studied with Single-Pair FRET." Biophysical Journal 98.3 (2010): 475a.
4. Berger, S.L. The complex language of chromatin regulation during transcription. Nature 447, 407–412 5. Carvalho, Sílvia, et al. "Histone methyltransferase SETD2 coordinates FACT recruitment with nucleosome
dynamics during transcription." Nucleic acids research 41.5 (2013): 2881-2893.6. "Pathology of Clear Cell Renal Cell Carcinoma ." Pathology of Clear Cell Renal Cell Carcinoma. N.p., n.d. Web. 17
Apr. 2013.7. Hu, M., X.-J. Sun, Y.-L. Zhang, Y. Kuang, C.-Q. Hu, W.-L. Wu, S.-H. Shen, T.-T. Du, H. Li, F. He, H.-S. Xiao, Z.-G. Wang,
T.-X. Liu, H. Lu, Q.-H. Huang, S.-J. Chen, and Z. Chen. "Histone H3 Lysine 36 Methyltransferase Hypb/Setd2 Is Required for Embryonic Vascular Remodeling." Proceedings of the National Academy of Sciences 107.7 (2010): 2956-961.
8. Sun, X.-J. "Identification and Characterization of a Novel Human Histone H3 Lysine 36-specific Methyltransferase." Journal of Biological Chemistry 280.42 (2005): 35261-5271.
9. Chen, Meng, et al. "Genome wide profiling of chromosomal alterations in renal cell carcinoma using high‐ ‐density single nucleotide polymorphism arrays."International Journal of Cancer 125.10 (2009): 2342-2348.