p57, Tumorigenesis, and Beckwith-Wiedemann Syndrome

Ashley Albright

p57 is a member of the Cip/Kip family of CKIs

• Encoded by CDKN1C• Cyclin/CDK binding domain • PAPA Repeat• QT domain

The ability of p57 to inhibit Cyclin/CDK suggests it is a tumor suppressor, however

p57 levels are high in some cancers

p57 inhibits proliferation by binding and inhibiting CDKs

• G1-S and G2-M transition

• Disruption of CDK/cyclin or PCNA binding region reduces ability of p57 to inhibit proliferation

p57 can suppress or promote apoptosis

• However, other data suggests p57 suppresses pro-apoptotic factors at cell cycle checkpoints

p57 and other Cip/Kip proteins promote cellular migration which leads to tumor

metastasis

p57 homozygous mutants cannot exit the cell cycle, allowing cells to become

over-proliferative

p57 misregulation can lead to cancer via many pathways

• DNA methylation and Histone Modifications

• MicroRNAs• Post-

translational Modification

CDKN1C has been implicated in Beckwith-Wiedemann Syndrome

• 1 in 12,000 newborns• Primarily due to improper imprinting• Classified as an overgrowth syndrome• Susceptible to tumors

BWS patients have a higher risk of developing abnormal tissue growth

References

• "Beckwith-Wiedemann Syndrome." Genetics Home Reference. Accessed March 30, 2015. http://ghr.nlm.nih.gov/condition/beckwith-wiedemann-syndrome.

• Bilodeau, S., et al. "Distinct Developmental Roles of Cell Cycle Inhibitors P57Kip2 and P27Kip1 Distinguish Pituitary Progenitor Cell Cycle Exit from Cell Cycle Reentry of Differentiated Cells." Molecular and Cellular Biology 29, no. 7 (2009): 1895-908.

• Cooper, W., et al. "Molecular Subtypes and Phenotypic Expression of Beckwith–Wiedemann Syndrome." European Journal of Human Genetics 13 (2005): 1025-032

• Denicourt, C., et al. "Cip/Kip Proteins: More than Just CDKs Inhibitors." Genes & Development 18 (2004): 851-55.

• Hatada, I., et al."An Imprinted Gene P57KIP2 Is Mutated in Beckwith–Wiedemann Syndrome." Nature Genetics 14 (1996): 171-73.

• Yan, Y., et al. "Ablation of the CDK Inhibitor P57 Kip2 Results in Increased Apoptosis and Delayed Differentiation during Mouse Development." Genes & Development 11 (1997): 973-83.