Report

AEC-Associated p63 Mutations Lead to Alternative Splicing/Protein Stabilization of p63 and Modulation of Notch Signaling

Volume 4, Issue 10   October 2005
Pages 1440 - 1447
http://dx.doi.org/10.4161/cc.4.10.2086
Authors: Yi-Ping Huang, Yuriy Kim, Zhaobo Li, Tanya Fomenkov, Alexey Fomenkov and Edward A. Ratovitski

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Abstract:
P63, the major regulator of epithelial development/differentiation, is mutated in human ectodermal dysplasias, such as ankyloblepharon, ectodermal dysplasia and clefting (AEC). We recently identified that p63? physically associated with mRNA processing/splicing proteins. We previously showed that p63 mutations mapped to the sterile ?-motif led to disruption of these interactions and modulated an aberrant splicing of keratinocyte growth factor receptor contributing into molecular mechanism underlying AEC phenotype.
To further investigate the molecular mechanisms associated with AEC syndrome we established the cellular model for this disorder by stable introduction of mutated allele [L514F] of p63? into immortalized keratinocyte cells. We showed that mutated ?Np63? mediated an aberrant splicing of its own p63 mRNA transcript, which in turn led to accumulation of proteasome-resistant C- terminal truncated p63. The truncated p63 failed to associate with the C-terminal domain of RNA polymerase II through SRA4 protein and, therefore affected keratinocyte proliferation, differentiation and survival and may strongly contribute to AEC phenotype.

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