Transcriptional Repression of miR-34 Family Contributes to p63-Mediated Cell Cycle Progression in Epidermal Cells
Transcriptional Repression of miR-34 Family Contributes to p63-Mediated Cell Cycle Progression in Epidermal Cells
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DOI：
10.1038/jid.2009.438
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发表时间：
2010-05-01
影响因子：
6.5
通讯作者：
Missero, Caterina
中科院分区：
文献类型：
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作者：
Antonini, Dario;Russo, Monia T.;Missero, Caterina
P63是P53家族成员，高表达于表皮的基底层增殖室，其表达与角质形成细胞的生长能力和再生能力密切相关。在这项研究中，我们报道了p63通过直接抑制miR-34a和miR-34c来维持细胞周期进展的机制。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的水平增加，伴随而来的是G1期停滞和细胞周期调节因子细胞周期蛋白d1和细胞周期蛋白依赖性激酶4(Cdk4)的抑制。P63直接与miR-34a和miR-34c调控区的P53一致位点结合，并抑制其活性。伴随着miR-34a和miR-34c的下调，细胞周期进程和细胞周期蛋白D1和CDK4的表达显著恢复。我们的数据表明，特定的miR-34家族成员在p63下游具有控制表皮细胞增殖的重要作用。
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.