p53-inducible Wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation

• Published in: The EMBO journal 2000-12, Vol.19 (23), p.6517-6526
• Main Authors: Takekawa, Mutsuhiro, Adachi, Masaaki, Nakahata, Atsuko, Nakayama, Ichiro, Itoh, Fumio, Tsukuda, Hiroyuki, Taya, Yoichi, Imai, Kohzoh
• Format: Article
• Language: English
• Subjects: Animals; Anisomycin - pharmacology; Antineoplastic Agents, Alkylating - pharmacology; Apoptosis; Blotting, Northern; Cell Nucleus - metabolism; COS Cells; dephosphorylation; DNA Damage; Dose-Response Relationship, Drug; Down-Regulation; Environmental stress; Enzyme Inhibitors - pharmacology; Gamma Rays; Glutathione Transferase - metabolism; Humans; Hydrogen peroxide; Hydrogen Peroxide - pharmacology; Imidazoles - pharmacology; Luciferases - metabolism; Methyl Methanesulfonate - pharmacology; Microscopy, Fluorescence; mitogen-activated protein kinase; Mitogen-Activated Protein Kinases - metabolism; Nucleic Acid Synthesis Inhibitors - pharmacology; p38; p38 Mitogen-Activated Protein Kinases; p38 protein; p53; Phosphorylation; Plant Proteins - physiology; Plasmids - metabolism; Precipitin Tests; protein phosphatase; Pyridines - pharmacology; Recombinant Fusion Proteins - metabolism; Serine - metabolism; Serine Proteinase Inhibitors; Signal Transduction; Threonine - metabolism; Time Factors; Transfection; Tumor Suppressor Protein p53 - metabolism; Ultraviolet radiation; Ultraviolet Rays; Wip1; Wip1 protein
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/19.23.6517

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. Wip1 was originally identified as a gene whose expression is induced following γ or UV radiation in a p53‐dependent manner. We found that Wip1 is also inducible by other environmental stresses, such as anisomycin, H 2 O 2 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.