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首页> 外文期刊>Molecular and Cellular Biology >An Autoregulatory Loop Directs the Tissue-Specific Expression of p63 through a Long-Range Evolutionarily Conserved Enhancer
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An Autoregulatory Loop Directs the Tissue-Specific Expression of p63 through a Long-Range Evolutionarily Conserved Enhancer

机译：自动调节环通过长距离进化保守增强子指导p63的组织特异性表达。

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摘要

p63, a p53 family member, is essential for the development of various stratified epithelia and is one of the earliest markers of many ectodermal structures, including the epidermis, oral mucosa, apical ectodermal ridge, and mammary gland. Genetic regulatory mechanisms controlling p63 spatial expression during development have not yet been defined. Using a genomic approach, we identified an evolutionarily conserved cis-regulatory element, located 160 kb downstream of the first p63 exon, which functions as a keratinocyte-specific enhancer and is sufficient to recapitulate expression of the endogenous gene during mouse embryogenesis. Dissection of the p63 enhancer activity revealed a positive autoregulatory loop in which the p63 proteins directly bind to and are essential regulators of the enhancer. Accordingly, transactivating p63 isoforms induce endogenous p63 expression in cells that do not normally express this gene, whereas dominant negative isoforms suppress p63 expression in keratinocytes. In addition the transcription factor AP-2 also binds to the enhancer and cooperates with p63 to induce its activity. These results demonstrate that a long-range autoregulatory loop is involved in the regulation of p63 expression during embryonic development and in adult cells.
机译：p63是p53家族成员，对于各种分层上皮细胞的发育必不可少，并且是许多表皮结构（包括表皮，口腔粘膜，根尖表皮和乳腺）的最早标记之一。在发育过程中控制 p63 空间表达的遗传调控机制尚未确定。使用基因组方法，我们确定了一个进化上保守的 cis 调控元件，位于第一个 p63 外显子下游160 kb，它可作为角质形成细胞特异的增强子，足以在小鼠胚胎发生过程中概括内源基因的表达。对 p63 增强子活性的剖析显示出一个正向的自调节循环，其中p63蛋白直接与增强子结合，并且是该增强子的基本调节子。因此，反式激活的p63亚型在通常不表达该基因的细胞中诱导内源性 p63 表达，而优势阴性亚型抑制角质形成细胞中 p63 表达。另外，转录因子AP-2也与增强子结合并与p63协同诱导其活性。这些结果表明，在胚胎发育过程中和成年细胞中， p63 表达的调控与远程自调控循环有关。

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