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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.

SUBMITTER: Candas D

PROVIDER: S-EPMC3656610 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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CyclinB1/Cdk1 phosphorylates mitochondrial antioxidant MnSOD in cell adaptive response to radiation stress.

Candas Demet D Fan Ming M Nantajit Danupon D Vaughan Andrew T AT Murley Jeffrey S JS Woloschak Gayle E GE Grdina David J DJ Li Jian Jian JJ

Journal of molecular cell biology 20121212 3

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 ([ ...[more]

PMID: 23243068

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Project description:BackgroundTo understand the molecular response of tumor cells to therapeutic ionizing radiation (IR), we previously reported that human breast cancer cells derived following chronic exposure to fractionated ionizing radiation (MCF+FIR) showed a transient radioresistance. MCF+FIR cells also demonstrated increased activity of NF-kappaB, increased expression of the mitochondrial antioxidant enzyme (MnSOD), and increased expression of a cell cycle regulatory protein (Cyclin B1). The present studies were designed to determine the relationship of NF-kappaB, MnSOD and Cyclin B1 expression in cellular adaptive responses to ionizing radiation.Materials and methodsThe first intron of the cyclin B1 gene with a putative NF-kappaB element was cloned into the pGL3 luciferase reporter (pGL3CB1EI1). PGL3CB1EI1 and control NF-kappaB luciferase activities were determined in MCF-7 and MCF+FIR cells treated with a single dose of radiation, over expression of the dominant negative mutant IkB (mIkB) or over expression of the SOD2 gene.ResultsMCF+FIR cells derived from fractionated IR demonstrated increased transactivation of the pGL3CB1EI1 and NF-kappaB controlled reporter activities, relative to the parental cell line. Transfection of dominant negative mutant IkB that inhibits NF-kappaB nuclear translocation, inhibited pGL3CB1EI1 and NF-kappaB activity, indicating the NF-kappaB dependence of pGL3CB1EI1 mediated transcription. In addition, over expression of the human SOD2 gene (MnSOD) inhibited NF-kappaB and pGL3CB1EI1 activity, indicating that superoxide or some species derived from superoxide may have participated in the up-regulation of reporter activity in response to chronic exposure to fractionated ionizing radiation. These results provide evidence suggesting that a signaling pathway involving NF-kappaB and Cyclin B1 may contribute to adaptive radioresistance induced by chronic exposure to fractionated IR and support the conclusion that MnSOD appears to be a negative regulator of this pathway.

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CyclinB1/Cdk1 phosphorylates mitochondrial antioxidant MnSOD in cell adaptive response to radiation stress.

Publications

CyclinB1/Cdk1 phosphorylates mitochondrial antioxidant MnSOD in cell adaptive response to radiation stress.

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