p53 homolog, p51/p63, maintains keratinocytes under undifferentiated state through suppression of Notch activity.

尽管基底角质形成细胞表达诱导角质形成细胞生长停滞和细胞分化的Notch 1，但它们保持未分化状态，提示在基底角质形成细胞中特异性地与Notch功能相互作用的未鉴定因子。p51，p53同源物，主要在基底角质形成细胞中表达，并且被认为不仅是角质形成干细胞的标志物，而且是表皮形成的先决条件。我们证明p51通过抑制Notch活性来维持未分化细胞的特征。显示Notch活性的HES-1启动子活性被Δ Np 51 B抑制，Δ Np 51 B是角质形成细胞中表达的主要p51亚型。有趣的是，TAp 51 B也发生了对HES-1启动子活性的类似抑制，预期TAp 51 B具有相反的分子功能，因为TA亚型具有反式激活结构域，而ΔN亚型没有。我们将p51腺病毒表达载体与Notch 1一起导入原代小鼠角质形成细胞，然后检测未分化细胞的特性。Δ Np 51 B可拮抗Notch 1诱导的生长停滞和整合素表达下调。p51的共表达恢复了针对Notch 1表达的未分化细胞特征。我们的数据表明，p51通过抑制Notch信号维持角质形成细胞的未分化状态，这种平衡与决定角质形成细胞的定型密切相关。

Although basal keratinocytes express Notch1 that induces growth arrest and cell differentiation in keratinocytes, they maintain undifferentiated state, suggestive of an unidentified factor(s) couteracting with Notch function specifically in basal keratinocytes. p51, p53 homolog, is expressed chiefly in basal keratinocytes, and is suggested as not only a marker for keratinocyte stem cells but also a prerequisite for the formation of epidermis. We demonstrate that p51 maintains undifferentiated cell characters through suppression of Notch activity. HES-1 promoter activity, showing Notch activity, was suppressed by ΔNp51B, the predominant p51 isoform expressed in keratinocytes. Interestingly, similar suppression of HES-1 promoter activity was also-occurred by TAp51B, which is expected to have opposite molecular functions because TA isoforms have transactivation domain while ΔN isoforms do not. We introduced p51 adenovirus expression vectors together with Notch1 into primary mouse keratinocytes, and then examined undifferentiated cell characters. ΔNp51B cancelled Notch1 induced growth arrest and downregulation of integrin expression. Co-expression of p51 restored undifferentiated cell characters against Notch1 expression. Our data reveal that p51 maintains undifferentiation condition of keratinocytes through the inhibition of Notch signal, and this balance tightly connects with determining keratinocyte cell commitment.