Lu Xiongbin, Nguyen Thuy-Ai, Donehower Lawrence A
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030, USA.
Cell Cycle. 2005 Aug;4(8):1060-4. Epub 2005 Aug 26.
The eukaryotic cell has evolved a sophisticated set of cell signaling pathways that respond to DNA damage and efficiently repair that damage, protecting the cell from deleterious mutations, genomic instability, and transformation into a cancerous state. The ATM and ATR serine/threonine kinases are key sensors and transducers of DNA damage signals through phosphorylation of an array of signaling molecules that mediate all aspects of the DNA damage response, including enforcement of cell cycle checkpoints and direct repair of damaged DNA. We have shown that a type 2C serine/threonine phosphatase, PPM1D (or Wip1), can reverse the phosphorylation status of ATM/ATR-phosphorylated proteins p53 and Chk1. This dephosphorylation of p53 and Chk1 by PPM1D may result in reduced functional activities and is accompanied by suppression of DNA damage-induced cell cycle checkpoints and some aspects of DNA repair. Because PPM1D is transcriptionally activated by p53 in response to DNA damage, PPM1D may serve as a critical component of a p53 negative feedback regulatory loop since it now appears that PPM1D can inhibit p53 activity by at least four different molecular mechanisms. This may explain why PPM1D is amplified and overexpressed in a subset of human breast cancers that invariably retain wild type p53 alleles. We hypothesize that PPM1D is a homeostatic regulator of the DNA damage response that returns the cell to a more normal unstressed state following repair of the damage.
真核细胞已经进化出一套复杂的细胞信号通路，这些通路能够对DNA损伤做出反应并有效修复损伤，保护细胞免受有害突变、基因组不稳定以及向癌状态转变的影响。ATM和ATR丝氨酸/苏氨酸激酶是DNA损伤信号的关键传感器和转导器，它们通过磷酸化一系列信号分子来介导DNA损伤反应的各个方面，包括实施细胞周期检查点以及直接修复受损DNA。我们已经表明，一种2C型丝氨酸/苏氨酸磷酸酶PPM1D（或Wip1）能够逆转ATM/ATR磷酸化蛋白p53和Chk1的磷酸化状态。PPM1D对p53和Chk1的这种去磷酸化作用可能导致功能活性降低，并伴随着DNA损伤诱导的细胞周期检查点的抑制以及DNA修复的某些方面。由于PPM1D在DNA损伤时被p53转录激活，PPM1D可能作为p53负反馈调节环的关键组成部分，因为现在看来PPM1D可以通过至少四种不同的分子机制抑制p53活性。这可能解释了为什么PPM1D在一部分始终保留野生型p53等位基因的人类乳腺癌中被扩增和过表达。我们假设PPM1D是DNA损伤反应的稳态调节因子，在损伤修复后使细胞恢复到更正常的无应激状态。
