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

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):
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):
Jirtle, Randy L., Jennifer Weidman. “Imprinted and more equal.” American Scientist 95 (2007):
Mainprize, Todd G. et al. “Cip/Kip cell-cycle inhibitors: A neuro-oncological perspective.” Journal of Neuro-Oncology 51 (2001):
Nakayama, Kei-ichi, Keiko Nakayama. “Cip/Kip cyclin-dependent kinase inhibitors: brakes of the cell cycle engine during development.” BioEssays (1998):

27. Questions