p53 and its homologues, p63 and p73, induce a replicative senescence through inactivation of NF-Y transcription factor
p53 and its homologues, p63 and p73, induce a replicative senescence through inactivation of NF-Y transcription factor
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DOI：
10.1038/sj.onc.1204748
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发表时间：
2001-09-13
期刊：
影响因子：
8
通讯作者：
Shin, DY
中科院分区：
文献类型：
--
作者：
Jung, MS;Yun, J;Shin, DY
最近的研究已经确定了两个p53同源物，p63和p73。当在某些人类肿瘤中过表达时，它们激活p53应答启动子并诱导细胞凋亡。在这里，我们报告说，p63，像p53和p73，诱导复制衰老时，在EJ细胞缺乏功能性p53四环素调控的方式表达。除了p53应答基因的转录激活外，我们发现p63和p73抑制cdk 1和细胞周期蛋白B基因的转录，这两种基因在衰老的人成纤维细胞中被不可逆地抑制。在瞬时转染试验中，p63和p73抑制cdk 1启动子，而不管p53的显性失活突变形式的存在。此外，我们发现，DNA结合活性的NF-γ转录因子，这是必不可少的cdk 1和细胞周期蛋白B基因的转录和失活的衰老成纤维细胞，是显着降低表达的p53，p63，或p73。由于NF-Y结合到除了cdk 1和细胞周期蛋白B启动子之外的许多启动子，因此p53家族基因对NF-Y的失活可能是复制性衰老中转录抑制的一般机制。
Recent studies have identified two p53 homologues, p63 and p73. They activate p53-responsive promoters and induce apoptosis when overexpressed in certain human tumors. Here, we report that p63, like p53 and p73, induces replicative senescence when expressed in a tetracycline-regulated manner in EJ cells lacking a functional p53. In addition to transcription activation of p53-responsive genes, we found that p63 and p73 repress transcription of the cdk1 and cyclin B genes, both of which are irreversibly repressed in senescent human fibroblast. In transient transfection assay, p63 and p73 repress the cdk1 promoter regardless of the presence of a dominant negative mutant form of p53. Furthermore, we found that DNA binding activity of NF-Y transcription factor, which is essential for transcription of the cdk1 and cyclin B genes and inactivated in senescent fibroblast, is significantly decreased by expression of either of p53, p63, or p73. Since NF-Y binds to many promoters besides the cdk1 and cyclin B promoters, inactivation of NF-Y by p53 family genes may be a general mechanism for transcription repression in replicative senescence.