Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation
Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation
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DOI：
10.1101/gad.1406006
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发表时间：
2006-04-15
影响因子：
10.5
通讯作者：
Dotto, GP
中科院分区：
文献类型：
--
作者：
Nguyen, BC;Lefort, K;Dotto, GP
Notch 信号传导促进角质形成细胞分化并抑制肿瘤发生。 p63 是 p53 家族成员，与角质形成细胞命运的建立和/或上皮自我更新的维持有关。在这里，我们表明，在小鼠和人类角质形成细胞中，Notch1 激活可通过一种独立于细胞周期退出的机制来抑制 p63 表达，并且需要下调选定的干扰素反应基因（包括 IRF7 和/或 IRF3）。反过来，p63 表达升高会抵消 Notch1 限制生长和促进分化的能力。 p63 作为 Notch 1 依赖性转录和功能的选择性调节剂，Hes-1 基因作为其直接负靶标之一。因此，Notch 和 p63 之间复杂的串扰涉及角质形成细胞自我更新和分化之间的平衡。
Notch signaling promotes commitment of keratinocytes to differentiation and suppresses tumorigenesis. p63, a p53 family member, has been implicated in establishment of the keratinocyte cell fate and/or maintenance of epithelial self-renewal. Here we show that p63 expression is suppressed by Notch1 activation in both mouse and human keratinocytes through a mechanism independent of cell cycle withdrawal and requiring down-modulation of selected interferon-responsive genes, including IRF7 and/or IRF3. In turn, elevated p63 expression counteracts the ability of Notch1 to restrict growth and promote differentiation. p63 functions as a selective modulator of Notch 1-dependent transcription and function, with the Hes-1 gene as one of its direct negative targets. Thus, a complex cross-talk between Notch and p63 is involved in the balance between keratinocyte self-renewal and differentiation.