title: CDK4-mediated MnSOD activation and mitochondrial homeostasis in radioadaptive protection.
abstract: Mammalian cells are able to sense environmental oxidative and genotoxic conditions such as the environmental low-dose ionizing radiation (LDIR) present naturally on the earth's surface. The stressed cells then can induce a so-called radioadaptive response with an enhanced cellular homeostasis and repair capacity against subsequent similar genotoxic conditions such as a high dose radiation. Manganese superoxide dismutase (MnSOD), a primary mitochondrial antioxidant in mammals, has long been known to play a crucial role in radioadaptive protection by detoxifying O2(•-) generated by mitochondrial oxidative phosphorylation. In contrast to the well-studied mechanisms of SOD2 gene regulation, the mechanisms underlying posttranslational regulation of MnSOD for radioprotection remain to be defined. Herein, we demonstrate that cyclin D1/cyclin-dependent kinase 4 (CDK4) serves as the messenger to deliver the stress signal to mitochondria to boost mitochondrial homeostasis in human skin keratinocytes under LDIR-adaptive radioprotection. Cyclin D1/CDK4 relocates to mitochondria at the same time as MnSOD enzymatic activation peaks without significant changes in total MnSOD protein level. The mitochondrial-localized CDK4 directly phosphorylates MnSOD at serine-106 (S106), causing enhanced MnSOD enzymatic activity and mitochondrial respiration. Expression of mitochondria-targeted dominant negative CDK4 or the MnSOD-S106 mutant reverses LDIR-induced mitochondrial enhancement and adaptive protection. The CDK4-mediated MnSOD activation and mitochondrial metabolism boost are also detected in skin tissues of mice receiving in vivo whole-body LDIR. These results demonstrate a unique CDK4-mediated mitochondrial communication that allows cells to sense environmental genotoxic stress and boost mitochondrial homeostasis by enhancing phosphorylation and activation of MnSOD.
authors.affiliation: Department of Radiation Oncology, University of California at Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Cuihong
authors.initials: C
authors.lastname: Jin
authors.affiliation: Department of Radiation Oncology, University of California at Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Qin
authors.affiliation: Department of Radiation Oncology, University of California at Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Radiation Oncology, University of California at Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Demet
authors.initials: D
authors.lastname: Candas
authors.affiliation: Department of Radiation Oncology, University of California at Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Fan
authors.affiliation: Department of Radiation Oncology, University of California at Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Chung-Ling
authors.initials: CL
authors.lastname: Lu
authors.affiliation: Department of Radiation Oncology, University of California at Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Andrew T M
authors.initials: AT
authors.lastname: Vaughan
authors.affiliation: Department of Pathology, Ohio State University Medical College, Columbus, OH 43210, USA.
authors.forename: Rulong
authors.initials: R
authors.lastname: Shen
authors.affiliation: Department of Radiation Oncology, University of California at Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Larry S
authors.initials: LS
authors.lastname: Wu
authors.affiliation: Department of Radiation Oncology, University of California at Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, University of California at Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Li
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Murley
authors.affiliation: Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Gayle
authors.initials: G
authors.lastname: Woloschak
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Grdina
authors.affiliation: Department of Radiation Oncology, University of California at Davis School of Medicine, Sacramento, CA 95817, USA; NCI-Designated Comprehensive Cancer Center, University of California at Davis Health System, Sacramento, CA, 95817, USA. Electronic address: jijli@ucdavis.edu.
authors.forename: Jian Jian
authors.initials: JJ
authors.lastname: Li
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D002460:Cell Line; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics* / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000201:enzymology / Q000528:radiation effects*; D053078:Membrane Potential, Mitochondrial / Q000528:radiation effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000201:enzymology / Q000528:radiation effects*; D010085:Oxidative Phosphorylation; D010766:Phosphorylation / Q000187:drug effects; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D014916:Whole-Body Irradiation
chemical_list: C530105:Ccnd1 protein, mouse; D019938:Cyclin D1; D013482:Superoxide Dismutase; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4
keywords: Cyclin D1/CDK4; Free radicals; Mitochondrial homeostasis; MnSOD; Phosphorylation; Radioadaptive response