1. P57Kip2 and Beckwith-Wiedemann Syndrome
Tim Lockney
P57Kip2 and Beckwith-Wiedemann Syndrome

2. What is p57? Alias: CDKN1C 316 Amino Acids long
Localized in the Nucleus
Important during development
Localized to Chromosome 11p15.5
Matsuoka et al.

3. What type of protein is p57?
CDK-inhibitor
p21 Family ? ?
Cip/Kip = CDK interacting protein/Kinase inhibitory protein
Has an NLS in the CDKi domain.
Siblings include p21 and p27
QT domain function is yet to be elucidated,
More complex structure suggests more roles.
The Cip/Kip proteins are intrinsically unstructured, adopting specific tertiary conformations only after binding to other
Proteins
This conformational flexibility suggests that phosphorylation
events and protein-protein interactions may modify
the folding of the CKIs, thereby modulating their ability to inhibit
cyclin-CDK complexes. Likewise, it may
explain why CKIs are capable of interacting with a wide diversity of proteins to regulate
various cellular functions.
Duronio, B.

4. p57 Function Negative regulator of cell cycle Tumor Suppressor!
Penultimately: CDK inhibitor
Ultimately a Tumor Suppressor
Specifically the G1-> S transition.
Mainprize, T.G. et al.

5. p57 Function Also involved in differentiation
Can act as a transcription factor
MyoD keeps myocyte a myocyte
The N-terminal cyclin-CDK binding region of p57 can interact with MyoD,
protecting MyoD from degradation
and thus promoting transactivation of muscle-specific genes
Besson, A. et al.

6. p57 Function Summary Tumor Suppressor Over expression = G1 arrest
Can bind to Proliferating Cell Nuclear Antigen (PCNA), a DNA polymerase Sigma processivity factor, via its C terminus (aa 143–160), thereby blocking processive DNA synthesis
Differentiation
Also involved in cytoskeletal dynamics and apoptosis, but involvement remains unclear.
So, as you can see, These proteins turn out to be MULTIFACETED
Segue into BWS

7. What is Beckwith-Wiedemann Syndrome?
1-13,000 or 1-15,000
COHEN JR., M.M.
Om-fowl-o-seal

8. BWS Tumors
Zhang, P. et al.
Larger kidney = more cells = more likelihood of cancer in absolute terms.
Cohen Jr., M.M.

9. Connecting BWS with p57 Knockout mice
Mainprize, T.G. et al.
none of the p57 knockouts lived past 2 weeks, and most died shortly after
birth. had BIRTH DEFECTS.
SHOW that MIDDLE IS HAPLOINSUFFICIENT!!
What Are the Birth defects? Segue into next slide
Zhang, P. et al.
Zhang, P. et al.

10. Knockout Mice Continued
Similarities
Zhang, P. et al.

11. How does p57 cause BWS? Imprinting: complex genetics
“A process that causes genes to be expressed according to their parental origin,”
Affects ~1000 human genes
The ones important for development
p57 is an imprinted gene.
P57 is not the only culprit, BWS is a pleiotropic diseases
Genomic imprinting is defined as an epigenetic modification of a
gene or the chromosome
Typically, imprinting results in monoallelic expression,
The cdkn1c gene is also an imprinted gene with preferred
expression of the maternal allele (Matsuoka et al., 1996), which
is recognized as a general mechanism to regulate embryonic
growth (Andrews et al., 2007). Importantly, p57 is the only CKI
to be required for embryonic development, as most mice lacking
the cdkn1c gene have multiple developmental abnormalities and
die at birth Some expression ~5% from paternal allele
- Andrew Feinberg – Imprinting of a Genomic Domain of llp15 and Loss of Imprinting in Cancer:
An Introduction

12. How does imprinting work?
Methylation
Histone Acetylation (chromatin modeling)
The cdkn1c gene is also an imprinted gene with preferred
expression of the maternal allele (Matsuoka et al., 1996), which
is recognized as a general mechanism to regulate embryonic
growth (Andrews et al., 2007). Importantly, p57 is the only CKI
to be required for embryonic development, as most mice lacking
the cdkn1c gene have multiple developmental abnormalities and
die at birth

13. Imprinting and BWS Normally Maternal p57 is expressed
Methylation is the main control
Methylation is green light
Uses methyl binding transcription factors
Many have normal karyotype, leads scientist to believe that LOI is the cause. Disruption of monoallelic expression.
LOI = cancer/bws
HETEROZYGOUS MICE THAT inherited a mutant allele from the mother manifested with
almost identical developmental anomolies as the homozygous knockout mice,
demonstrating that the locus is imprinted.

14. LOI LOI can occur via LOH LOM Or even a bad gene
White oval is unmethylated, black oval is methylated.
Bad genes, can be deletions or even point mutations.
LOSS OF METHYLATION IS THE MOST COMMON CAUSE OF BWS ~50%
Chromosomes in the egg conserve histones whereas histones are replaced by protamines in sperm
HETEROZYGOUS MICE THAT inherited a mutant allele from the mother manifested with
almost identical developmental anomolies as the homozygous knockout mice,
demonstrating that the locus is imprinted.
K. Higashimoto et al.
Izuho Hatada et al.

15. MENTION TEST TUBE BABIES! Tx’s? Intravenous solutions for hypoglycemia
This is why I’m hot.
MENTION TEST TUBE BABIES!
Tx’s? Intravenous solutions for hypoglycemia
Toungue resection
Cancer treatment
Hatada I. et al.

16. Questions?