title: Direct activation of ATM by resveratrol under oxidizing conditions.
abstract: Resveratrol has been widely reported to reduce cancer progression in model systems and to selectively induce cell death in transformed cell lines. Many enzymes have been reported to respond to resveratrol in mammalian cells, including the Ataxia-Telangiectasia Mutated (ATM) protein kinase that acts in DNA damage recognition, signaling, and repair. Here we investigate the responses of ATM to resveratrol exposure in normal and transformed human cell lines and find that ATM autophosphorylation and substrate phosphorylation is stimulated by resveratrol in a manner that is promoted by reactive oxygen species (ROS). We observe direct stimulatory effects of resveratrol on purified ATM in vitro and find that the catalytic efficiency of the kinase on a model substrate is increased by resveratrol. In the purified system we also observe a requirement for oxidation, as the effect of resveratrol on ATM signaling is substantially reduced by agents that prevent disulfide bond formation in ATM. These results demonstrate that resveratrol effects on ATM are direct, and suggest a mechanism by which the oxidizing environment of transformed cells promotes ATM activity and blocks cell proliferation.
authors.affiliation: The Howard Hughes Medical Institute, The Department of Molecular Biosciences, and the Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Ji-Hoon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, United States of America, and the Department of Genetics, Harvard University Medical School, Boston, Massachusetts, United States of America and the Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Guo
authors.affiliation: The Howard Hughes Medical Institute, The Department of Molecular Biosciences, and the Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Logan R
authors.initials: LR
authors.lastname: Myler
authors.affiliation: The Howard Hughes Medical Institute, The Department of Molecular Biosciences, and the Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Suting
authors.initials: S
authors.lastname: Zheng
authors.affiliation: The Howard Hughes Medical Institute, The Department of Molecular Biosciences, and the Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Tanya T
authors.initials: TT
authors.lastname: Paull
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D001761:Bleomycin / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism*; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D016877:Oxidants; D017382:Reactive Oxygen Species; D013267:Stilbenes; D001761:Bleomycin; D006861:Hydrogen Peroxide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D000077185:Resveratrol