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: Synthesis of cyclins Phosphorylation – both inhibitory and stimulatory CDK inhibitory proteins (CKIs)

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

CKIs

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

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

Knock-out Mice

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

Imprinting

Imprinting and Cancer

Imprinting and Cancer

Beckwith-Wiedemann Syndrome

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

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

Associated Tumors Wilms Tumor Hepatoblastoma Neuroblastoma Rhabdomyosarcoma

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

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

The Role of p57 in BWS/Cancer

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

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

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

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

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

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

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