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AEC-Associated p63 Mutations Lead to Alternative Splicing/Protein Stabilization of p63 and Modulation of Notch Signaling
Yi-Ping Huang, Yuriy Kim, Zhaobo Li, Tanya Fomenkov, Alexey Fomenkov and Edward A. Ratovitski
volume 4 | issue 10
october 2005Pages: 1440 - 1447
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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.
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.