title: CyclinB1/Cdk1 phosphorylates mitochondrial antioxidant MnSOD in cell adaptive response to radiation stress.
abstract: Manganese superoxide dismutase (MnSOD), a major antioxidant enzyme within the mitochondria, is responsible for the detoxification of free radicals generated by cellular metabolism and environmental/therapeutic irradiation. Cell cycle-dependent kinase Cdk1, along with its regulatory partner CyclinB1, plays important roles in the regulation of cell cycle progression as well as in genotoxic stress response. Herein, we identified the presence of the minimal Cdk1 phosphorylation consensus sequence ([S/T]-P; Ser106) in human MnSOD, suggesting Cdk1 as a potential upstream kinase of MnSOD. A substantial amount of CyclinB1/Cdk1 was found to localize in the mitochondrion upon irradiation. The enhanced Cdk1/MnSOD interaction and MnSOD phosphorylation were detected in both the irradiated human cells and mouse tissues. We report that CyclinB1/Cdk1 can regulate MnSOD through reversible Ser106 phosphorylation, both in vivo and in vitro. The CyclinB1/Cdk1-mediated MnSOD Ser106 resulted in increased MnSOD activity and stability, along with improved mitochondrial function and cellular resistance to radiation-induced apoptosis. These results demonstrate a unique pro-survival mechanism by which cells enhance the survival via CyclinB1/Cdk1-mediated MnSOD activation under genotoxic stress conditions.
authors.affiliation: Department of Radiation Oncology, University of California at Davis, Sacramento, CA 95817, USA.
authors.forename: Demet
authors.initials: D
authors.lastname: Candas
authors.forename: Ming
authors.initials: M
authors.lastname: Fan
authors.forename: Danupon
authors.initials: D
authors.lastname: Nantajit
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Vaughan
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Murley
authors.forename: Gayle E
authors.initials: GE
authors.lastname: Woloschak
authors.forename: David J
authors.initials: DJ
authors.lastname: Grdina
authors.forename: Jian Jian
authors.initials: JJ
authors.lastname: Li
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D056744:Cyclin B1 / Q000378:metabolism*; D004249:DNA Damage; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism / Q000528:radiation effects*; D010766:Phosphorylation; D021381:Protein Transport; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D056744:Cyclin B1; D013482:Superoxide Dismutase; D016203:CDC2 Protein Kinase