CEINGE Biotecnologie Avanzate, Napoli, Italy.
J Invest Dermatol. 2010 May;130(5):1249-57. doi: 10.1038/jid.2009.438. Epub 2010 Jan 21.
p63, a p53 family member, is highly expressed in the basal proliferative compartment of the epidermis and its expression has been correlated with the growth ability and regenerative capacity of keratinocytes. In this study we report a mechanism through which p63 maintains cell cycle progression by directly repressing miR-34a and miR-34c. In the absence of p63, increased levels of miR-34a and miR-34c were observed in primary keratinocytes and in embryonic skin, with concomitant G1-phase arrest and inhibition of the cell cycle regulators cyclin D1 and cyclin-dependent kinase 4 (Cdk4). p63 directly bound to p53-consensus sites in both miR-34a and miR-34c regulatory regions and inhibited their activity. Concomitant downregulation of miR-34a and miR-34c substantially restored cell cycle progression and expression of cyclin D1 and Cdk4. Our data indicate that specific miR-34 family members have a significant role downstream of p63 in controlling epidermal cell proliferation.
p63 是 p53 家族的一员，在表皮的基底层增殖区高度表达，其表达与角质形成细胞的生长能力和再生能力相关。在这项研究中，我们报告了一种通过直接抑制 miR-34a 和 miR-34c 来维持细胞周期进程的机制。在没有 p63 的情况下，在原代角质形成细胞和胚胎皮肤中观察到 miR-34a 和 miR-34c 的水平升高，同时发生 G1 期阻滞和细胞周期调节剂细胞周期蛋白 D1 和细胞周期蛋白依赖性激酶 4（Cdk4）的抑制。p63 直接结合到 miR-34a 和 miR-34c 调节区域的 p53 共识位点上，并抑制它们的活性。miR-34a 和 miR-34c 的同时下调显著恢复了细胞周期进程和细胞周期蛋白 D1 和 Cdk4 的表达。我们的数据表明，特定的 miR-34 家族成员在控制表皮细胞增殖方面在 p63 的下游具有重要作用。
