Defective induction but normal activation and function of p53 in mouse cells lacking poly-ADP-ribose polymerase
Defective induction but normal activation and function of p53 in mouse cells lacking poly-ADP-ribose polymerase
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DOI：
10.1038/sj.onc.1201274
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发表时间：
1997-08-28
期刊：
影响因子：
8
通讯作者：
Stark, GR
中科院分区：
文献类型：
--
作者：
Agarwal, ML;Agarwal, A;Stark, GR
Poly-ADP-ribose聚合酶(PARP)和p53浴引起的DNA损伤和每个提出了调解损害正常细胞反应,我们发现从PARP-null小鼠胚胎成纤维细胞有一个类似于双重的p53的基础水平低,p53诱导的DNA损伤反应或核苷酸损耗超过两个小于正常老鼠细胞,这些因素加在一起,减少诱导水平由4-5-fold PARP-deficient p53蛋白的细胞,然而，与正常细胞相比，PARP缺陷细胞中p53活性的诱导几乎没有减少，用p53响应启动子进行检测。此外，与缺乏p53的细胞相比，缺乏PARP的细胞在DNA损伤后通常在G(1)中阻滞，而缺乏p53的细胞则没有这个检查点。其他依赖p53的特性，如有丝分裂纺锤体检查点和基因扩增的许可性，在PARP缺陷细胞中也是正常的。我们得出结论，p53蛋白的诱导水平受parp依赖和parp独立途径的组合控制，p53的激活在很大程度上是parp独立的，结果与p53对基因表达的调节既包括蛋白量的增加，也包括p53作为转录因子的激活的模型一致。
Poly-ADP-ribose polymerase (PARP) and p53 are bath induced by DNA damage and each has been proposed to mediate the normal cellular response to damage, We find that embryo fibroblasts from PARP-null mice have a similar to twofold lower basal level of p53 and that the induction of p53 in response to DNA damage or nucleotide depletion is more than twofold less than in normal mouse cells, These factors combine to decrease the induced level of the p53 protein in PARP-deficient cells by 4-5-fold, compared to normal cells, However, there is virtually no decrease in the induction of p53 activity in PARP-deficient cells, as assayed with a p53-responsive promoter, Furthermore, cells lacking PARP arrest normally in G(1) after DNA damage, in contrast to cells lacking p53, where this checkpoint is absent, Other p53-dependent properties, such as the mitotic spindle checkpoint and permissivity for gene amplification, are also normal in PARP-deficient cells, We conclude that the induced level of the p53 protein is governed by a combination of PARP-dependent and PARP-independent pathways and that the activation of p53 is largely PARP-independent, The results are consistent with a model in which the regulation of gene expression by p53 involves both increases in the amount of the protein and activation of p53 as a transcription factor.