p53-inducible wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation.
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 gamma 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.
Takekawa
M
M
First Department of Internal Medicine, Sapporo Medical University, School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Japan. takekawa@ims.u-tokyo.ac.jp
Adachi
M
M
Nakahata
A
A
Nakayama
I
I
Itoh
F
F
Tsukuda
H
H
Taya
Y
Y
Imai
K
K
D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis; D015152:Blotting, Northern; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005720:Gamma Rays; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D010940:Plant Proteins / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011725:Pyridines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015842:Serine Proteinase Inhibitors; D015398:Signal Transduction; D013912:Threonine / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases
D018906:Antineoplastic Agents, Alkylating; D004791:Enzyme Inhibitors; D007093:Imidazoles; D019384:Nucleic Acid Synthesis Inhibitors; D010940:Plant Proteins; D011725:Pyridines; D011993:Recombinant Fusion Proteins; D015842:Serine Proteinase Inhibitors; D016159:Tumor Suppressor Protein p53; C082799:WIP1 protein, Zea mays; D013912:Threonine; D012694:Serine; D000841:Anisomycin; D008741:Methyl Methanesulfonate; D006861:Hydrogen Peroxide; D008156:Luciferases; D005982:Glutathione Transferase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580