p53 homologue, p51/p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity
p53 homologue, p51/p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity
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DOI：
10.1038/sj.onc.1210235
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发表时间：
2007-07-01
期刊：
影响因子：
8
通讯作者：
Ikawa, S.
中科院分区：
文献类型：
--
作者：
Okuyama, R.;Ogawa, E.;Ikawa, S.
p53 同源物 p51/p63 主要在角质形成细胞干细胞中表达，对于表皮的形成是不可或缺的。 Notch1 是该过程中不可或缺的另一个基因，可诱导角质形成细胞生长停滞和分化。我们发现，Delta Np51B (Delta Np63 α)（一种在基底角质形成细胞中特异性表达的 p51 异构体）的外源表达，通过抑制 p21 表达和维持整合素表达，阻断了小鼠角质形成细胞中 Notch 1 依赖性生长停滞和分化。此外，发现DNp51B本身具有诱导整合素α6β4表达的能力，从而促进基底细胞附着至基底膜，从而使细胞保持未成熟状态。因此，我们得出结论，即使在 Notch1 的影响下，DNp51B 的表达也保证了整合素的表达，并且 Delta Np51B 是通过抑制 Notch1 活性来维持基底细胞角质形成细胞不成熟所需的长期寻找的因子。我们将假设一个合理的模型来解释鳞状上皮结构的维持，并为皮肤病的病理特征提供机械解释，包括癌症、牛皮癣以及生理性伤口愈合。
p53 homologue, p51/p63, predominantly expressed in keratinocyte stem cells, is indispensable for the formation of epidermis. Notch1, another such gene indispensable for the process, induces growth arrest and differentiation in keratinocytes. We found that exogenous expression of Delta Np51B (Delta Np63 alpha), one of the isoforms of p51 specifically expressed in basal keratinocytes, blocked Notch 1-dependent growth arrest and differentiation in mouse keratinocytes by inhibiting p21 expression and maintaining integrins expression. Furthermore, DNp51B by itself was found to have ability to induce expression of integrin alpha 6 beta 4, which promotes attachment of basal cells to basal membrane thereby keeping the cells in immature state. Therefore, we conclude that DNp51B expression warrants integrin expression even under the influence of Notch1 and that Delta Np51B is a long-sought factor required to maintain basal cell keratinocytes immaturity by inhibiting Notch1 activity. We will postulate a plausible model explaining the maintenance of the squamous epithelium architectures as well as offering mechanistic explanations for pathological features of skin diseases, including cancers, psoriasis along with physiological wound healings.