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p57 & Beckwith-Weidemann Syndrome

p57 & Beckwith-Weidemann Syndrome. Claire Conn. Outline. Normal Function of p57 Beckwith-Weidemann Syndrome Relationship of p57 to cancer. The Role of p57 in the Cell. Remember CDKs?. Cyclin-CDK complexes are important regulators of the cell cycle They are regulated in 3 ways:

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p57 & Beckwith-Weidemann Syndrome

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  1. p57 & Beckwith-Weidemann Syndrome Claire Conn

  2. Outline • Normal Function of p57 • Beckwith-Weidemann Syndrome • Relationship of p57 to cancer

  3. The Role of p57 in the Cell

  4. Remember CDKs? • Cyclin-CDK complexes are important regulators of the cell cycle • They are regulated in 3 ways: • Synthesis of cyclins • Phosphorylation – both inhibitory and stimulatory • CDK inhibitory proteins (CKIs)

  5. INK4 Family (p16 family) Inhibitors of CDK4 Selectively inhibit only CDK4/6 p16INK4a, p15INK4b, p18INK4c, p19INK4d Cip/Kip Family (p21 family) CDK interacting protein/Kinase inhibitory protein Inhibit any of the cyclin-CDK complexes p21Cip1, p27Kip1, p57Kip2 p21 p21 CDK CDK Cyclin Cyclin p16 CDK4 CDK4 Cyclin p16 CKIs

  6. CKIs

  7. Cip/Kip Inhibitors • Inhibit cyclin-CDK complexes by inhibiting kinase activity by blocking ATP. • All are candidates as tumor suppressor genes

  8. Why do we need 3 of them? • Redundancy • Variation in response and activity • p21 is induced by p53 to mediate G1 arrest in response to DNA damage • p27 is induced by cell-cell contact to mediate contact inhibition • p57 is involved in early development especially organogenesis

  9. Knock-out Mice

  10. p57 • Has an effect on cells to exit the cell cycle • Not all the defects are linked to cellular proliferation suggesting it has other roles than as a CKI • Genomically imprinted with the maternal allele being preferentially expressed in most tissues • Found on chromosome 11 in a cluster of imprinted genes (including IGF-2) • High expression during embryogenesis and decreases to low levels in adulthood

  11. Imprinting

  12. Imprinting and Cancer

  13. Imprinting and Cancer

  14. Beckwith-Wiedemann Syndrome

  15. BWS • Congenital overgrowth disorder causing large body size and large organs. • Usually sporadic but may be inherited. • Multigenic disorder • Increased rate of tumor development

  16. Clinical Characteristics • Macroglossia • Large, protruding eyes • Abdominal wall defects • Umbilical hernia • Omphalocele • Pitted Ear lobes • Hypoglycemia • Heart defects • Cleft palate • Enlarged organs • Kidney, liver, spleen

  17. Associated Tumors • Wilms Tumor • Hepatoblastoma • Neuroblastoma • Rhabdomyosarcoma

  18. Etiology • Dysregulation of alleles in the chromosome region 11p15.5

  19. Treatment • Most treatment involves treating the symptoms • IV solutions for hypoglycemia • Surgery to remove congenital tumors • Surgery to reduce tongue size to obtain an open airway • Periodic screenings for evidence of associated tumors

  20. The Role of p57 in BWS/Cancer

  21. p57 and Cancer • Maternal allele loss of p57 is involved with some cases of BWS as well as a variety of tumors • In BWS mutations were found in the CDK binding domain and the nuclear localizing region

  22. p57 and BWS • p57 knockout mice have a lot of overlapping symptoms with BWS • Only ~5% of BWS cases have a mutation in p57 • Other mechanisms for silencing p57 and/or other genes are involved with the development of BWS

  23. Possible causes for BWS • Loss of imprinting of IGF-2 • Loss of function of p57 • Trisomy with paternal duplication • Maternally inherited translocations

  24. p57 and IGF-2 • Double mutant study • Found characteristics of BWS not seen in other mouse models • BWS symptoms more severe than in either single mutant

  25. Review • p57 is a CKI that is genomically imprinted and functions mostly during embryonic development regulating organogenesis • BWS is a congenital overgrowth disorder • p57 is a tumor suppressor and loss of function results in increased proliferation

  26. References Caspary, Tamara et al. “Oppositely imprinted genes p57kip2 and Igf2 interact in a mouse model for Beckwith-Wiedemann Syndrome.” Genes and Development 13 (1999): 3115-3124. Gaston, V. et al. “Gene Mutation in Beckwith-Wiedemann Syndrome.” Hormone Research 54 (2000): 1-5. Hatada, I. et al. “New p57 mutations in Beckwith-Wiedemann Syndrome.” Human Genetics 100 (1997): 681-683. Jirtle, Randy L., Jennifer Weidman. “Imprinted and more equal.” American Scientist 95 (2007): 143-149 Mainprize, Todd G. et al. “Cip/Kip cell-cycle inhibitors: A neuro-oncological perspective.” Journal of Neuro-Oncology 51 (2001): 205-218. Nakayama, Kei-ichi, Keiko Nakayama. “Cip/Kip cyclin-dependent kinase inhibitors: brakes of the cell cycle engine during development.” BioEssays 20.12 (1998): 1020-1029. http://www.emedicine.com/ped/topic218.htm http://www.gfmer.ch/genetic_diseases_v2/gendis_detail_list.php?cat3=40

  27. Questions

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