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首页> 外文期刊>Cell cycle >AEC-associated p63 mutations lead to alternative splicing/protein stabilization of p63 and modulation of Notch signaling.
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AEC-associated p63 mutations lead to alternative splicing/protein stabilization of p63 and modulation of Notch signaling.

机译：AEC相关的p63突变导致p63的可变剪接/蛋白稳定和Notch信号的调节。

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摘要

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 p63alpha physically associated with mRNA processing/splicing proteins. We previously showed that p63 mutations mapped to the sterile alpha-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 p63alpha into immortalized keratinocyte cells. We showed that mutated DeltaNp63alpha 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.
机译：p63是上皮发育/分化的主要调节因子，在人外胚层发育异常中发生了突变，例如：甲胎龙，外胚层发育异常和裂口（AEC）。我们最近发现，p63alpha与mRNA加工/剪接蛋白物理相关。我们以前表明，映射到无菌α-基序的p63突变导致这些相互作用的破坏，并调节了角质形成细胞生长因子受体的异常剪接，这是潜在的AEC表型的分子机制。为了进一步研究与AEC综合征相关的分子机制，我们通过将p63alpha的突变等位基因[L514F]稳定引入永生化的角质形成细胞中，建立了该疾病的细胞模型。我们表明，突变的DeltaNp63alpha介导了其自身p63 mRNA转录的异常剪接，进而导致耐蛋白酶体的C端截短的p63积累。截短的p63不能通过SRA4蛋白与RNA聚合酶II的C末端结构域缔合，因此影响了角质形成细胞的增殖，分化和存活，可能对AEC表型有重要贡献。

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