1. Tim Lockney

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/Kinase inhibitory protein http://www.getreligion.org/wp- content/photos/Face_of_RPI___que stion_mark.gif Duronio, B.

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

5. p57 Function  Also involved in differentiation  Can act as a transcription factor  MyoD keeps myocyte 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 Cohen Jr., M.M. http://images.google.com/imgres?imgurl=http://www.nlm.nih.gov/medlineplus/ency/image s/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.

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

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

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  Histone Acetylation (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 via LOH  LOM  Or even a bad gene Izuho Hatada et al. K. Higashimoto et al.

15. Hatada I. et al.

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