P57KIP2 AND BECKWITH-

WIEDEMANN SYNDROME

Tim Lockney

What is p57?

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

What type of protein is p57?

CDK-inhibitor p21 Family

? ?

Cip/Kip = CDK interacting protein/Kinase inhibitory protein

http://www.getreligion.org/wp-content/photos/Face_of_RPI___question_mark.gif

Duronio, B.

p57 Function Negative regulator

of cell cycle Tumor Suppressor!

http://www.genome.jp/dbget-bin/show_pathway?hsa04110+1028

Mainprize, T.G. et al.

p57 Function Also involved in

differentiation Can act as a

transcription factor MyoD keeps

myocyte a myocyteBesson, A. et al.

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.

What is Beckwith-Wiedemann Syndrome?

1-13,000 or 1-15,000

http://beckwith-wiedemannsyndrome.org/graphics/uploadfile/1276/dia_0025a_.jpg

COHEN JR., M.M.

BWS Tumors

Cohen Jr., M.M. http://images.google.com/imgres?imgurl=http://www.nlm.nih.gov/medlineplus/ency/images/ency/fullsize/9056.jpg&imgrefurl=http://www.nlm.nih.gov/medlineplus/ency/imagepages/9056.htm&h=320&w=400&sz=11&hl=en&start=1&um=1&tbnid=9gfxNPL-LdXZGM:&tbnh=99&tbnw=124&prev=/images%3Fq%3Dwilm%2527s%2Btumor%26um%3D1%26hl%3Den%26safe%3Doff%26client%3Dfirefox-a%26rls%3Dorg.mozilla:en-US:official%26sa%3DN

Zhang, P. et al.

Connecting BWS with p57

Knockout mice

Zhang, P. et al.

Zhang, P. et al.

Mainprize, T.G. et al.

Knockout Mice Continued Similarities

Zhang, P. et al.

http://ez-host.org/graphics/uploadfile/1276/omphalocele_.jpg

How does p57 cause BWS? Imprinting: complex genetics “A process that causes genes to be

expressed according to their parental origin,”

Affects ~1000 human genesThe ones important for development

p57 is an imprinted gene.

How does imprinting work? Methylation Histone Acetylation (chromatin modeling)

http://genome.wellcome.ac.uk/assets/GEN10000675.jpg

Imprinting and BWS Normally Maternal p57 is expressed Methylation is the main control Methylation is green light

Uses methyl binding transcription factors

LOI LOI can occur via

LOH LOM Or even a bad gene

Izuho Hatada et al. K. Higashimoto et al.

Hatada I. et al.

Questions?

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