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P57 Kip2 and Beckwith- Wiedemann Syndrome

Tim Lockney. P57 Kip2 and Beckwith- Wiedemann Syndrome . 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 p 21 Family ? ?

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P57 Kip2 and Beckwith- Wiedemann Syndrome

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  1. Tim Lockney P57Kip2and Beckwith-Wiedemann Syndrome

  2. What is p57? • Alias: CDKN1C • 316 Amino Acids long • Localized in the Nucleus • Important during development • Localized to Chromosome 11p15.5 Matsuoka et al.

  3. What type of protein is p57? • CDK-inhibitor • p21 Family? ? • Cip/Kip = CDK interacting protein/Kinaseinhibitory protein Duronio, B. http://www.getreligion.org/wp-content/photos/Face_of_RPI___question_mark.gif

  4. p57 Function • Negative regulator of cell cycle • Tumor Suppressor! Mainprize, T.G. et al. http://www.genome.jp/dbget-bin/show_pathway?hsa04110+1028

  5. p57 Function • Also involved in differentiation • Can act as a transcription factor • MyoD keepsmyocyte a myocyte Besson, A. et al.

  6. 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.

  7. 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.

  8. BWS Tumors Zhang, P. et al. 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

  9. Connecting BWS with p57 • Knockout mice Mainprize, T.G. et al. Zhang, P. et al. Zhang, P. et al.

  10. Knockout Mice Continued • Similarities http://ez-host.org/graphics/uploadfile/1276/omphalocele_.jpg Zhang, P. et al.

  11. How does p57 cause BWS? • Imprinting: complex genetics • “A process that causes genes to be expressed according to their parental origin,” • Affects ~1000 human genes • The ones important for development • p57 is an imprinted gene.

  12. How does imprinting work? • Methylation • HistoneAcetylation (chromatin modeling) http://genome.wellcome.ac.uk/assets/GEN10000675.jpg

  13. Imprinting and BWS • Normally Maternal p57 is expressed • Methylation is the main control • Methylation is green light • Uses methyl binding transcription factors

  14. LOI • LOI can occur viaLOH • LOM • Or even a bad gene K. Higashimoto et al. IzuhoHatada et al.

  15. Hatada I. et al.

  16. Questions? http://flickr.com/photos/46883783@N00/page4/

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