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首页> 外文期刊>Cell cycle >The Hay Wells syndrome-derived TAp63alphaQ540L mutant has impaired transcriptional and cell growth regulatory activity.
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The Hay Wells syndrome-derived TAp63alphaQ540L mutant has impaired transcriptional and cell growth regulatory activity.

机译:Hay Hays综合征衍生的TAp63alphaQ540L突变体损害了转录和细胞生长调节活性。

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摘要

p63 mutations have been associated with several human hereditary disorders characterized by ectodermal dysplasia such as EEC (ectrodactyly, ectodermal dysplasia, clefting) syndrome, ADULT (acro, dermato, ungual, lacrimal, tooth) syndrome and AEC (ankyloblepharon, ectodermal dysplasia, clefting) syndrome (also called Hay-Wells syndrome). The location and functional effects of the mutations that underlie these syndromes reveal a striking genotype-phenotype correlation. Unlike EEC and ADULT that result from missense mutations in the DNA-binding domain of p63, AEC is solely caused by missense mutations in the SAM domain of p63. In this paper we report a study on the TAp63alpha isoform, the first to be expressed during development of the embryonic epithelia, and on its naturally occurring Q540L mutant derived from an AEC patient. To assess the effects of the Q540L mutation, we generated stable cell lines expressing TAp63alpha wt, DeltaNp63alpha or the TAp63alpha-Q540L mutant protein and used them to systematically compare the cell growth regulatory activity of the mutant and wt p63 proteins and to generate, by microarray analysis, a comprehensive profile of differential gene expression. We found that the Q540L substitution impairs the transcriptional activity of TAp63alpha and causes misregulation of genes involved in the control of cell growth and epidermal differentiation.
机译:p63突变与几种人类遗传性疾病有关,这些疾病的特征在于外胚层发育异常,例如EEC(外胚层发育异常,外胚层发育异常,c裂)综合征,ADULT(Acro,皮肤,舌,舌,泪,牙齿)综合征和AEC(甲状ble虫,外胚层发育不良,c裂)综合征(也称为Hay-Wells综合征)。这些综合症基础突变的位置和功能影响揭示了惊人的基因型-表型相关性。与p63的DNA结合域中的错义突变导致的EEC和ADULT不同,AEC仅由p63的SAM域中的错义突变引起。在本文中,我们报告了一项关于TAp63alpha亚型的研究,该亚型是在胚胎上皮细胞的发育过程中首次表达的,并且是对AEC患者的Q540L天然突变体的研究。为了评估Q540L突变的影响,我们生成了表达TAp63alpha wt,DeltaNp63alpha或TAp63alpha-Q540L突变蛋白的稳定细胞系,并使用它们来系统比较该突变体和wt p63蛋白的细胞生长调节活性,并通过微阵列产生分析,全面介绍差异基因表达。我们发现,Q540L取代会损害TAp63alpha的转录活性,并导致与细胞生长和表皮分化控制有关的基因失调。

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