p53-inducible Wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation
p53-inducible Wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation
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DOI：
10.1093/emboj/19.23.6517
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发表时间：
2000-12-01
期刊：
影响因子：
11.4
通讯作者：
Imai, K
中科院分区：
文献类型：
--
作者：
Takekawa, M;Adachi, M;Imai, K
应激反应的p38MAPK，当被紫外线辐射等遗传毒性应激激活时，通过磷酸化增强P53的活性，导致细胞周期停滞或细胞凋亡。在此，我报道了蛋白磷酸酶2C家族的成员Wip1在受损细胞的恢复期下调p38-p53信号的作用。Wip1最初被认为是一种基因，其表达是在伽马或紫外线照射后以P53依赖的方式诱导的。我们发现Wip1还可以被其他环境胁迫诱导，如山奈霉素、H_2O_2和甲基甲烷磺酸盐。紫外线诱导Wip1除了野生型P53外，还需要p38活性。Wip1通过其保守的苏氨酸残基的特异性去磷酸化来选择性地灭活p38。此外，Wip1的表达减弱了紫外线诱导的P53在Ser33和Ser46的磷酸化，先前报道的残基是由p38磷酸化的。Wip1的表达还抑制了P53介导的转录和紫外线辐射诱导的细胞凋亡。这些结果表明，Wip1的P53依赖性表达介导了p38-P53信号的负反馈调节，并有助于抑制紫外线诱导的细胞凋亡。
The stress-responsive p38 MAPK, when activated by genotoxic stresses such as UV radiation, enhances p53 activity by phosphorylation and leads to cell cycle arrest or apoptosis. Here me report that a member of the protein phosphatase type 2C family, Wip1, has a role in down-regulating p38-p53 signaling during the recovery phase of the damaged cells. Wip1 was originally identified as a gene whose expression is induced following gamma or UV radiation in a p53-dependent manner. We found that Wip1 is also inducible by other environmental stresses, such as anisomycin, H2O2 and methyl methane sulfonate. UV-induction of Wip1 requires p38 activity in addition to the wild-type p53. Wip1 selectively inactivates p38 by specific dephosphorylation of its conserved threonine residue. Furthermore, Wip1 expression attenuates UV-induced p53 phosphorylation at Ser33 and Ser46, residues previously reported to be phosphorylated by p38. Wip1 expression also suppresses both p53-mediated transcription and apoptosis in response to UV radiation. These results suggest that p53-dependent expression of Wip1 mediates a negative feedback regulation of p38-p53 signaling and contributes to suppression of the UV-induced apoptosis.