Here we investigate activation of the p53 pathway by inhibition of transcription. Comparison of cells with either mutant p53 or wt p53 indicated that inhibition of p53- dependent transcription is necessary and sufficient for wt p53 accumulation. In addition to Mdm-2, p21 is required for effective p53 degradation. Transient inhibition of transcription resulted in initial downregulation of p21 and Mdm-2 leading to accumulation of wt p53. This was followed by induction of p21 and Mdm-2, normalization of p53 levels, and p21-dependent growth arrest. Although simultaneous induction of p53 and p21 could be detected by immunoblot, levels of p53 and p21 were discordant in individual cells. By inducing p21 and Mdm-2, p53 discriminates between transient and sustained inhibition of transcription. Transient inhibition results in p21-dependent growth, while sustained inhibition of transcription leads to p53-facilitated cell death. One can envision p53 as a physiological sensor of transcriptional integrity. Transient inhibition of p53- stimulated transcription by numerous stimuli including nucleotide depletion, hypoxia, UV light may be an prevalent mechanism of activation of wt p53 and its downstream pathways.

译文

在这里,我们研究通过抑制转录激活p53途径。与突变型p53或wt p53的细胞比较表明,抑制p53依赖性转录对于wt p53的积累是必要且足够的。除Mdm-2外,p21是有效的p53降解所必需的。转录的瞬时抑制导致p21和Mdm-2的初始下调,导致wt p53的积累。随后是p21和Mdm-2的诱导,p53水平的正常化以及p21-dependent的生长停滞。尽管可以通过免疫印迹检测到p53和p21的同时诱导,但单个细胞中p53和p21的水平不一致。通过诱导p21和Mdm-2,p53区分转录的瞬时和持续抑制。瞬时抑制导致p21-dependent生长,而持续抑制转录导致p53-facilitated细胞死亡。人们可以设想p53作为转录完整性的生理传感器。许多刺激 (包括核苷酸耗竭,缺氧,紫外线) 对p53刺激的转录的瞬时抑制可能是wt p53及其下游途径激活的普遍机制。

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