CDK4-mediated MnSOD activation and mitochondrial homeostasis in radioadaptive protection
| Autor: | Rulong Shen, Lili Qin, Gayle E. Woloschak, Andrew T M Vaughan, Ming Fan, Robert F. Li, Jeffrey S. Murley, Jian Jian Li, Demet Candas, David J. Grdina, Yan Shi, Rui Liu, Cuihong Jin, Chung Ling Lu, Larry S. Wu |
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| Rok vydání: | 2015 |
| Předmět: |
Keratinocytes
MnSOD Ionizing animal diseases Cellular homeostasis Free radicals Genotoxic Stress Mitochondrion Medical Biochemistry and Metabolomics Biochemistry Radiation Tolerance Oxidative Phosphorylation Mice Radiation Ionizing Post-translational regulation Cyclin D1 Radioadaptive response Phosphorylation Inbred BALB C Membrane Potential Mitochondrial Mice Inbred BALB C Radiation Adaptation Physiological Cell biology Mitochondria Mitochondrial Signal transduction Whole-Body Irradiation Signal Transduction Biochemistry & Molecular Biology Physiological SOD2 Mitochondrial homeostasis Oxidative phosphorylation Biology Membrane Potential Article Cell Line Superoxide dismutase Dose-Response Relationship Medicinal and Biomolecular Chemistry Physiology (medical) Genetics Animals Humans Adaptation Superoxide Dismutase fungi Cyclin-Dependent Kinase 4 Dose-Response Relationship Radiation Molecular biology enzymes and coenzymes (carbohydrates) Gene Expression Regulation biology.protein Cyclin D1/CDK4 Biochemistry and Cell Biology |
| Zdroj: | Jin, C; Qin, L; Shi, Y; Candas, D; Fan, M; Lu, CL; et al.(2015). CDK4-mediated MnSOD activation and mitochondrial homeostasis in radioadaptive protection. Free Radical Biology and Medicine, 81, 77-87. doi: 10.1016/j.freeradbiomed.2014.12.026. UC Davis: Retrieved from: http://www.escholarship.org/uc/item/9hn5k0f4 |
| DOI: | 10.1016/j.freeradbiomed.2014.12.026. |
| Popis: | © 2015 Elsevier Inc. All rights reserved. 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. |
| Databáze: | OpenAIRE |
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