p 57 & Beckwith- Wiedemann syndrome (BWS)
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Transcript of p 57 & Beckwith- Wiedemann syndrome (BWS)
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By: Adam Drechsler
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p57(kip2) is a CDK inhibitor
Cyclin
CDK p57
Cyclin
CDK p57
Cyclin D
CDK4 p16 CDK4
p16Ink4 Inhibitors
Cip/Kip Proteins
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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
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p57 Mouse Knockout
Targeted disruption of mouse p57(kip2) gene.
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In the absence of p57…
p57 -/- : Embryonic/neonatal lethality, multiple developmental defects, altered cell proliferation and differentiation.
p57 +/- : Same as above, orWild-type expression
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Genomic Imprinting Gene expressed in a parent-of-origin specific manner. Paternal imprint of p57
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To add to the complexity… Highly variable penetrance
Displays subset of all phenotypes.
85% sporadic
CDKInhibitor Domain
ProlineRichDomain
AcidicDomain
QT Domain
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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
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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.
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Additional BWS information Good prognosis
Children usually grow up to become normal heights.
Mortality Risk Infant Mortality < 20%
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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.