Chromosome Stability group, Laboratory of Molecular Genetics, The National Institute for Environmental and Health Sciences, Research Triangle Park, N.C., United States of America.
Front Biosci (Landmark Ed). 2012 Jan 1;17(4):1480-98. doi: 10.2741/3999.
Wip1 (PPM1D) is a stress responsive PP2C phosphatase that plays a key role in stress signaling. Although originally identified as a gene induced by p53 after genotoxic stress, we now know that Wip1 expression is additionally regulated by other mechanisms. Wip1 is not only a target of p53, but is also a target of other transcription factors, including Estrogen Receptor-alpha and NF-kappaB. Additionally, Wip1 expression is regulated by post-transcriptional mechanisms such as mRNA stabilization and alternative splicing. Upon induction, Wip1 dampens the stress response by dephosphorylating and inactivating proteins such as p53, p38 MAPK, and ATM, usually as part of a negative feedback loop. As a result, Wip1 functions to abrogate cell cycle checkpoints and inhibit senescence, apoptosis, DNA repair, and the production of inflammatory cytokines. Furthermore, Wip1 is overexpressed in several types of human cancers and has oncogenic functions. The regulation of Wip1, the role of Wip1 in stress signaling, and the cooperation of Wip1 with oncogenes in promoting tumorigenesis will be discussed in this review.
Wip1（PPM1D）是一种应激反应性 PP2C 磷酸酶，在应激信号转导中发挥关键作用。尽管最初被鉴定为 p53 在遗传毒性应激后诱导的基因，但我们现在知道 Wip1 的表达还受到其他机制的调节。Wip1 不仅是 p53 的靶标，也是其他转录因子（包括雌激素受体-α和 NF-κB）的靶标。此外，Wip1 的表达受转录后机制的调节，如 mRNA 稳定和选择性剪接。诱导后，Wip1 通过去磷酸化和失活 p53、p38 MAPK 和 ATM 等蛋白来抑制应激反应，通常作为负反馈环的一部分。因此，Wip1 的功能是消除细胞周期检查点并抑制衰老、凋亡、DNA 修复和炎性细胞因子的产生。此外，Wip1 在多种人类癌症中过度表达，并具有致癌功能。本综述将讨论 Wip1 的调节、Wip1 在应激信号转导中的作用以及 Wip1 与致癌基因在促进肿瘤发生中的合作。
