P57KIP2 AND BECKWITH-
WIEDEMANN SYNDROME
Tim Lockney
What is p57?
Alias: CDKN1C 316 Amino Acids long Localized in the Nucleus Important during development Localized to Chromosome 11p15.5 Matsuoka et al.
What type of protein is p57?
CDK-inhibitor p21 Family
? ?
Cip/Kip = CDK interacting protein/Kinase inhibitory protein
http://www.getreligion.org/wp-content/photos/Face_of_RPI___question_mark.gif
Duronio, B.
p57 Function Negative regulator
of cell cycle Tumor Suppressor!
http://www.genome.jp/dbget-bin/show_pathway?hsa04110+1028
Mainprize, T.G. et al.
p57 Function Also involved in
differentiation Can act as a
transcription factor MyoD keeps
myocyte a myocyteBesson, A. et al.
p57 Function Summary Tumor Suppressor Over expression = G1 arrest Can bind to Proliferating Cell Nuclear
Antigen (PCNA), a DNA polymerase Sigma processivity factor, via its C terminus (aa 143–160), thereby blocking processive DNA synthesis
Differentiation Also involved in cytoskeletal dynamics and
apoptosis, but involvement remains unclear.
What is Beckwith-Wiedemann Syndrome?
1-13,000 or 1-15,000
http://beckwith-wiedemannsyndrome.org/graphics/uploadfile/1276/dia_0025a_.jpg
COHEN JR., M.M.
BWS Tumors
Cohen Jr., M.M. http://images.google.com/imgres?imgurl=http://www.nlm.nih.gov/medlineplus/ency/images/ency/fullsize/9056.jpg&imgrefurl=http://www.nlm.nih.gov/medlineplus/ency/imagepages/9056.htm&h=320&w=400&sz=11&hl=en&start=1&um=1&tbnid=9gfxNPL-LdXZGM:&tbnh=99&tbnw=124&prev=/images%3Fq%3Dwilm%2527s%2Btumor%26um%3D1%26hl%3Den%26safe%3Doff%26client%3Dfirefox-a%26rls%3Dorg.mozilla:en-US:official%26sa%3DN
Zhang, P. et al.
Connecting BWS with p57
Knockout mice
Zhang, P. et al.
Zhang, P. et al.
Mainprize, T.G. et al.
Knockout Mice Continued Similarities
Zhang, P. et al.
http://ez-host.org/graphics/uploadfile/1276/omphalocele_.jpg
How does p57 cause BWS? Imprinting: complex genetics “A process that causes genes to be
expressed according to their parental origin,”
Affects ~1000 human genesThe ones important for development
p57 is an imprinted gene.
How does imprinting work? Methylation Histone Acetylation (chromatin modeling)
http://genome.wellcome.ac.uk/assets/GEN10000675.jpg
Imprinting and BWS Normally Maternal p57 is expressed Methylation is the main control Methylation is green light
Uses methyl binding transcription factors
LOI LOI can occur via
LOH LOM Or even a bad gene
Izuho Hatada et al. K. Higashimoto et al.
Hatada I. et al.
Questions?
http://flickr.com/photos/46883783@N00/page4/