title: Wip1 suppresses apoptotic cell death through direct dephosphorylation of BAX in response to γ-radiation.
abstract: Wild-type p53-induced phosphatase 1 (Wip1) is a p53-inducible serine/threonine phosphatase that switches off DNA damage checkpoint responses by the dephosphorylation of certain proteins (i.e. p38 mitogen-activated protein kinase, p53, checkpoint kinase 1, checkpoint kinase 2, and uracil DNA glycosylase) involved in DNA repair and the cell cycle checkpoint. Emerging data indicate that Wip1 is amplified or overexpressed in various human tumors, and its detection implies a poor prognosis. In this study, we show that Wip1 interacts with and dephosphorylates BAX to suppress BAX-mediated apoptosis in response to γ-irradiation in prostate cancer cells. Radiation-resistant LNCaP cells showed dramatic increases in Wip1 levels and impaired BAX movement to the mitochondria after γ-irradiation, and these effects were reverted by a Wip1 inhibitor. These results show that Wip1 directly interacts with and dephosphorylates BAX. Dephosphorylation occurs at threonines 172, 174 and 186, and BAX proteins with mutations at these sites fail to translocate efficiently to the mitochondria following cellular γ-irradiation. Overexpression of Wip1 and BAX, but not phosphatase-dead Wip1, in BAX-deficient cells strongly reduces apoptosis. Our results suggest that BAX dephosphorylation of Wip1 phosphatase is an important regulator of resistance to anticancer therapy. This study is the first to report the downregulation of BAX activity by a protein phosphatase.
authors.affiliation: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Asan, Seoul, Korea.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Song
authors.forename: S-H
authors.initials: SH
authors.lastname: Ryu
authors.forename: Y M
authors.initials: YM
authors.lastname: Cho
authors.forename: Y S
authors.initials: YS
authors.lastname: Kim
authors.forename: B-M
authors.initials: BM
authors.lastname: Lee
authors.forename: S-W
authors.initials: SW
authors.lastname: Lee
authors.forename: J
authors.initials: J
authors.lastname: Choi
mesh_terms: D017209:Apoptosis / Q000528:radiation effects*; D004249:DNA Damage; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000502:physiology*; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D011836:Radiation Tolerance; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: C494826:BAX protein, human; D051028:bcl-2-Associated X Protein; D048031:JNK Mitogen-Activated Protein Kinases; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C
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