title: RAC2-P38 MAPK-dependent NADPH oxidase activity is associated with the resistance of quiescent cells to ionizing radiation.
abstract: Our recent study showed that quiescent G0 cells are more resistant to ionizing radiation than G1 cells; however, the underlying mechanism for this increased radioresistance is unknown. Based on the relatively lower DNA damage induced in G0 cells, we hypothesize that these cells are exposed to less oxidative stress during exposure. As a catalytic subunit of NADPH oxidase, Ras-related C3 botulinum toxin substrate 2 (RAC2) may be involved in the cellular response to ionizing radiation. Here, we show that RAC2 was expressed at low levels in G0 cells but increased substantially in G1 cells. Relative to G1 cells, the total antioxidant capacity in G0 phase cells increased upon exposure to X-ray radiation, whereas the intracellular concentration of ROS and malondialdehyde increased only slightly. The induction of DNA single- and double-stranded breaks in G1 cells by X-ray radiation was inhibited by knockdown of RAC2. P38 MAPK interaction with RAC2 resulted in a decrease of functional RAC2. Increased phosphorylation of P38 MAPK in G0 cells also increased cellular radioresistance; however, excessive production of ROS caused P38 MAPK dephosphorylation. P38 MAPK, phosphorylated P38 MAPK, and RAC2 regulated in mutual feedback and negative feedback regulatory pathways, resulting in the radioresistance of G0 cells.
authors.affiliation: a School of Radiation Medicine and Protection, Medical College of Soochow University , Suzhou , China.|b Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions , Suzhou , China.|f Institute of Space Life Sciences, Soochow University , Suzhou , China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Pei
authors.affiliation: a School of Radiation Medicine and Protection, Medical College of Soochow University , Suzhou , China.|b Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions , Suzhou , China.|f Institute of Space Life Sciences, Soochow University , Suzhou , China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: a School of Radiation Medicine and Protection, Medical College of Soochow University , Suzhou , China.|b Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions , Suzhou , China.|f Institute of Space Life Sciences, Soochow University , Suzhou , China.
authors.forename: Jing
authors.initials: J
authors.lastname: Nie
authors.affiliation: c Department of Space Radiobiology , Institute of Modern Physics, Chinese Academy of Sciences , Lanzhou , China.
authors.forename: Nan
authors.initials: N
authors.lastname: Ding
authors.affiliation: a School of Radiation Medicine and Protection, Medical College of Soochow University , Suzhou , China.|b Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions , Suzhou , China.|f Institute of Space Life Sciences, Soochow University , Suzhou , China.
authors.forename: Wentao
authors.initials: W
authors.lastname: Hu
authors.affiliation: c Department of Space Radiobiology , Institute of Modern Physics, Chinese Academy of Sciences , Lanzhou , China.
authors.forename: Junrui
authors.initials: J
authors.lastname: Hua
authors.affiliation: d Research Center for Charged Particle Therapy, National Institutes for Quanturn and Radiological Science and Technology , Chiba , Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Hirayama
authors.affiliation: d Research Center for Charged Particle Therapy, National Institutes for Quanturn and Radiological Science and Technology , Chiba , Japan.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Furusawa
authors.affiliation: d Research Center for Charged Particle Therapy, National Institutes for Quanturn and Radiological Science and Technology , Chiba , Japan.
authors.forename: Cuihua
authors.initials: C
authors.lastname: Liu
authors.affiliation: a School of Radiation Medicine and Protection, Medical College of Soochow University , Suzhou , China.|b Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions , Suzhou , China.
authors.forename: Bingyan
authors.initials: B
authors.lastname: Li
authors.affiliation: a School of Radiation Medicine and Protection, Medical College of Soochow University , Suzhou , China.|e Center for Radiological Research, College of Physician and Surgeons, Columbia University , New York , NY , USA.
authors.forename: Tom K
authors.initials: TK
authors.lastname: Hei
authors.affiliation: a School of Radiation Medicine and Protection, Medical College of Soochow University , Suzhou , China.|b Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions , Suzhou , China.|f Institute of Space Life Sciences, Soochow University , Suzhou , China.
authors.forename: Guangming
authors.initials: G
authors.lastname: Zhou
mesh_terms: D002453:Cell Cycle / Q000528:radiation effects*; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair / Q000528:radiation effects; D016193:G1 Phase / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D009249:NADP / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D010766:Phosphorylation / Q000528:radiation effects; D034741:RNA, Small Interfering / Q000378:metabolism; D011836:Radiation Tolerance / Q000528:radiation effects*; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000528:radiation effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D000097766:RAC2 GTP-Binding Protein
chemical_list: D009249:NADP; D019255:NADPH Oxidases; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins; D000097766:RAC2 GTP-Binding Protein
keywords: NADPH oxidase; RAC2; quiescent cells; radiosensitivity; reactive oxygen species