p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumor cells
p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumor cells
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DOI：
10.1101/gad.10.19.2438
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发表时间：
1996-10-01
影响因子：
10.5
通讯作者：
Prives, C
中科院分区：
文献类型：
--
作者：
Chen, XB;Ko, LJ;Prives, C
已经确定，细胞中p53肿瘤抑制蛋白的诱导可以导致细胞周期停滞或细胞凋亡。为了进一步了解p53的功能，有助于这些细胞反应的几个p53无效Saos 2和H1299细胞系，表达野生型或突变形式的p53，或细胞周期蛋白依赖性激酶抑制剂p21/WAF 1，在四环素调控的启动子。我们的研究结果表明，细胞水平的p53可以决定细胞的反应，使较低水平的p53导致逮捕，而较高的水平导致细胞凋亡;然而，DNA损伤可以提高细胞对p53的凋亡反应，而不改变细胞中p53的蛋白水平。我们还表明，逮捕和凋亡是两个基因分离的功能p53，因为转录不称职的p53可以诱导凋亡，但不逮捕，而诱导p21/WAF 1，这是一个主要的转录靶点的p53，可以诱导逮捕，但不凋亡。最后，我们表明，一个完整的凋亡反应p53需要浴其氨基和羧基末端，我们的数据表明，有转录依赖性和非依赖性的功能p53在细胞凋亡之间的协同作用。因此，有多种独立的细胞对p53的反应，这些反应一起可以解释不同类型的人类肿瘤中p53突变的异常高频率。这些结果的影响进行了讨论，并提出了一个模型。
It is well established that induction of the p53 tumor suppressor protein in cells can lead to either cell cycle arrest or apoptosis. To further understand features of p53 that contribute to these cell responses several p53-null Saos2 and H1299 cell lines were generated that express wild-type or mutant forms of p53, or the cyclin-dependent kinase inhibitor p21/WAF1, under a tetracycline-regulated promoter. Our results show that the cellular level of p53 can dictate the response of the cell such that lower levels of p53 result in arrest whereas higher levels result in apoptosis; nevertheless, DNA damage can heighten the apoptotic response to p53 without altering the protein level of p53 in cells. We also demonstrate that arrest and apoptosis are two genetically separable functions of p53 because a transcriptionally incompetent p53 can induce apoptosis but not arrest, whereas induction of p21/WAF1, which is a major transcriptional target of p53, can induce arrest but not apoptosis. Finally, we show that a full apoptotic response to p53 requires bath its amino and carboxyl terminus, and our data suggest that there is synergism between transcription-dependent and -independent functions of p53 in apoptosis. Thus, there are multiple independent cellular responses to p53 that together may account for the extraordinarily high frequency of p53 mutations in diverse types of human tumors. The implications of these results are discussed and a model is proposed.