p57Kip2 Beckwith-Wiedemann Syndrome

Chris JoubertMarch 31, 2005

Beckwith-Wiedemann Syndrome (BWS)

•Hans-Rudolf Wiedemann (1964) and J. Bruce Beckwith (1969)•Congenital exomphalos, macroglossia, and gigantism •In the US: US frequency is estimated at 1 in 15,000 live births. •Children affected with BWS have a propensity to develop tumors such as Wilms’ tumor, hepatoblastoma, and rhabdomyosarcomas.

http://www.emedicine.com/ped/topic218.htm

Mainprize et al. (2001) J Neuro-Oncol 51:205-218

Beckwith-Wiedemann Syndrome

•Approximately 80% of BWS patients demonstrate genotypic abnormalities of the distal region of chromosome arm 11p •The BWS region of 11p was the first identified example of imprinting in mammals •Several 11p genes are imprinted, including p57, IGF2, and H19.

http://www.emedicine.com/ped/topic218.htmMainprize et al. (2001) J Neuro-Oncol 51:205-218

Maternal Paternal

Imprinting

Only one allele is expressed

p57 - Lessons from Knockout Mice

Mainprize et al. (2001) J Neuro-Oncol 51:205-218

Nakayama et al. (1998) BioEssays 20:1020-1029

P57-/- - Embryonic/neonatal lethality,Multiple developmental defects,altered cellular proliferation

Mice Knockouts

Similarities to BWS

•Omphalocele

•Enlargement of the adrenal cortex, adrenal cytomegaly, and renal medullary dysplasia

Zhang et al. (1997) Nature 387:151-158

p57

•Member of family of Cip/Kip inhibitors along with p21Cip1 and p27Kip2

•Inhibit wide range of CDKs and bind to both the cyclin and cyclin-dependant kinase.•Cip/Kip inhibitors are not specific to any particular cyclin/CDK complex.

Mainprize et al. (2001) J Neuro-Oncol 51:205-218

p57

CDK Inhibitory Domain

Proline Rich Domain

Acidic Domain

QT Domain

•316 Amino-acids•Performs majority of function in nucleus and contains nuclear localizing sequences at C-terminal end.

Mainprize et al. (2001) J Neuro-Oncol 51:205-218

Nakayama et al. (1998) BioEssays 20:1020-1029

Russo et al. (1996) Nature 382:325

CDK Inhibitory Domain

Cyclin A

CDK2

Russo et al. (1996) Nature 382:325

•CDK inhibitory domain binds conserved cyclin box of cyclin and binds CDK, occupying its catalytic cleft

p57Kip2

Cyclin D/ E

CDK 4/2

Courtesy of Dr. Duronio

Mainprize et al. (2001) J Neuro-Oncol 51:205-218

p57

How does this relate to cancer?

p57 and cancer

•P57Kip2 localizes to chromosome 11p15.5, a region containing several imprinted genes.•Paternal allele of p57Kip2 is transcriptionally silent in mice and humans.•800 Kbp centromeric to the gene encoding insulin-like growth factor-2 (IGF-2), which is also imprinted and expressed only by the paternal allele

Mainprize et al. (2001) J Neuro-Oncol

Mechanisms for downregulation of p57 in BWS

•Maternally inherited mutations• 5-10% - sporadic• 30-50% - familial

•IGF-2 downregulates mRNA expression of p57Kip2

-Increased levels of IGF-2 caused by one of three possible events:

1) Mutation in Igf2R gene – IGF2R decreases levels of IGF-2

2) Loss of imprinting (LOI) of IGF-23) Inherit 2 paternal alleles

Joyce et al. (1997) Hum. Mol. Genet. 6:1543Mainprize et al. (2001) J Neuro-Oncol

p57Kip2

Cyclin D/ E

CDK 4/2

Courtesy of Dr. Duronio

Mainprize et al. (2001) J Neuro-Oncol 51:205-218

•Exomphalos, macroglossia, gigantism•Mouse knockouts•Cip/Kip inhibitor•Cancer

•Complete loss•Chronic low levels

Summary