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

p53 同源物 p51/p63 通过抑制 Notch 活性将角质形成细胞维持在未分化状态。

基本信息

批准号：
15591166
负责人：
OKUYAMA Ryuhei
金额：
$ 2.24万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591166/
关键词：
Notch p51 p53 Keratinocytes Epithelial cells Differentiation 細胞増殖転写因子シグナル伝達発癌乾癬

项目摘要

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.

尽管基底角质形成细胞表达Notch1，诱导生长停滞和细胞分化，但它们保持未分化状态，这表明在基底角质形成细胞中有一种未知的因子特异性地与Notch功能相抵消。P51， p53的同系物，主要在基底角化细胞中表达，被认为不仅是角化细胞干细胞的标记物，也是表皮形成的先决条件。我们证明p51通过抑制Notch活性维持未分化的细胞特性。hes1启动子活性，显示Notch活性，被ΔNp51B（角化细胞中主要表达的p51亚型）抑制。有趣的是，TAp51B也会对HES-1启动子活性产生类似的抑制，这可能具有相反的分子功能，因为TA异构体具有转激活结构域，而ΔN异构体则没有。我们将p51腺病毒表达载体与Notch1一起导入小鼠原代角质形成细胞，检测未分化细胞的特性。ΔNp51B取消了Notch1诱导的生长停滞和整合素表达下调。p51的共表达恢复了Notch1表达的未分化细胞特性。我们的数据显示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细胞承诺密切相关。