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.