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- Title
p53-inducible Wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation.
- Authors
Takekawa, Mutsuhiro; Adachi, Masaaki; Nakahata, Atsuko; Nakayama, Ichiro; Itoh, Fumio; Tsukuda, Hiroyuki; Taya, Yoichi; Imai, Kohzoh
- Abstract
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 we 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. Wipl was originally identified as a gene whose expression is induced following γ or UV radiation in a p53-dependent manner. We found that Wipl is also inducible by other environmental stresses, such as anisomycin, H202 and methyl methane sulfonate. UV-induction of Wipl requires p38 activity in addition to the wild-type p53. Wipl selectively inactivates p38 by specific dephosphorylation of its conserved threonine residue. Furthermore, Wipl expression attenuates UV-induced p53 phosphorylation at Ser33 and Ser46, residues previously reported to be phosphorylated by p38. Wipl expression also suppresses both p53-mediated transcription and apoptosis in response to UV radiation. These results suggest that p53-dependent expression of Wipl mediates a negative feedback regulation of p38-p53 signaling and contributes to suppression of the UV-induced apoptosis.
- Subjects
GENETIC toxicology; RADIATION; PHOSPHORYLATION; PROTEINS; CELL cycle; GENE expression; TRANSCRIPTION factors; APOPTOSIS
- Publication
EMBO Journal, 2000, Vol 19, Issue 23, p6517
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1093/emboj/19.23.6517