p 57 & beckwith- wiedemann syndrome (bws)

By: Adam Drechsler

p57(kip2) is a CDK inhibitor

Cyclin

CDK p57

Cyclin

CDK p57

Cyclin D

CDK4 p16 CDK4

p16Ink4 Inhibitors

Cip/Kip Proteins

p57- location of action

p57 is:

-A tumor suppressor

-Localized to chromosome 11p15

-Down regulated by IGF-2

-An inhibitor of G1 Cyclin-CDK complexes

-At low levels a stimulator of cycD-CDK4/6

p57 Mouse Knockout

Targeted disruption of mouse p57(kip2) gene.

In the absence of p57…

p57 -/- : Embryonic/neonatal lethality, multiple developmental defects, altered cell proliferation and differentiation.

p57 +/- : Same as above, orWild-type expression

Genomic Imprinting Gene expressed in a parent-of-origin specific manner. Paternal imprint of p57

To add to the complexity… Highly variable penetrance

Displays subset of all phenotypes.

85% sporadic

CDKInhibitor Domain

ProlineRichDomain

AcidicDomain

QT Domain

Complex pattern of inheritance 15% of cases are familial

Autosomal dominant inheritance with variable expressivity (if mutated allele is inherited from mother)

Uniparental disomyTrisomy of chromosome 11p15.5Duplication of this chromosomeTranslocations involving maternal 11p.15.5

Beckwith-Wiedemann Syndrome

Growth abnormalities Somatic Overgrowth Macroglossia Gigantism Enlarged adrenal glands Ear creases Visceromegaly (enlarged organs) Omphalocele (umbilical hernia) Kidney abnormalities Advanced aging Birth weight and height > 90 percentile 1000-fold increase in risk of devloping childhood tumors.

Additional BWS information Good prognosis

Children usually grow up to become normal heights.

Mortality Risk Infant Mortality < 20%

Summary p57 is a cip/kip inhibitor p57 inhibits action by cyclin/cdk complexes

and prevents transition from G1 to S The paternal p57 gene is imprinted. p57 is high during embryogenesis and its

expression decreases toward adulthood 85% of cases are sporadic Loss of p57 function is the cause of

Beckwith-Wiedemann syndrome IGF-2 may play a role in the development

of BWS.