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p 57 & Beckwith- Wiedemann syndrome (BWS)

p 57 & Beckwith- Wiedemann syndrome (BWS). By: Adam Drechsler. CDK. CDK. Cyclin. Cyclin. CDK4. CDK4. Cyclin D. p16. p16. p57(kip2) is a CDK inhibitor. Ink4 Inhibitors. p57. Cip/Kip Proteins. p57. p57- location of action. p57 is : -A tumor suppressor

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p 57 & Beckwith- Wiedemann syndrome (BWS)

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  1. p57 & Beckwith-Wiedemann syndrome (BWS) By: Adam Drechsler

  2. CDK CDK Cyclin Cyclin CDK4 CDK4 Cyclin D p16 p16 p57(kip2) is a CDK inhibitor Ink4 Inhibitors p57 Cip/Kip Proteins p57

  3. 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

  4. p57 Mouse Knockout • Targeted disruption of mouse p57(kip2) gene.

  5. In the absence of p57… • p57 -/- : Embryonic/neonatal lethality, multiple developmental defects, altered cell proliferation and differentiation. • p57 +/- : • Same as above, or • Wild-type expression

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

  7. To add to the complexity… • Highly variable penetrance • Displays subset of all phenotypes. • 85% sporadic CDK Inhibitor Domain Proline Rich Domain Acidic Domain QT Domain

  8. Complex pattern of inheritance • 15% of cases are familial • Autosomal dominant inheritance with variable expressivity (if mutated allele is inherited from mother) • Uniparental disomy • Trisomy of chromosome 11p15.5 • Duplication of this chromosome • Translocations involving maternal 11p.15.5

  9. 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.

  10. Additional BWS information • Good prognosis • Children usually grow up to become normal heights. • Mortality Risk • Infant Mortality < 20%

  11. 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.

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