title: RhoA GTPase oxidation stimulates cell proliferation via nuclear factor-κB activation.
abstract: Reactive oxygen species (ROS) produced by many kinds of stimuli are essential for cellular signaling including cell proliferation. The dysregulation of ROS, therefore, is related to a variety of diseases including cancer. However, it was not clearly elucidated how ROS regulate cell proliferation and tumorigenesis. In this study, we investigated a mechanism by which the oxidation of RhoA GTPase regulates nuclear factor-κB (NF-κB) and cell proliferation. Hydrogen peroxide activated NF-κB and RhoA GTPase, but did not activate RhoA C16/20A mutant, an oxidation-resistant form. Remarkably, the oxidation of RhoA reduced its affinity towards RhoGDI, leading to the dissociation of RhoA-RhoGDI complex. Si-Vav2, a guanine nucleotide exchange factor (GEF), inhibited RhoA activation upon hydrogen peroxide. The oxidized RhoA (oxRhoA)-GTP was readily bound to IκB kinase γ (IKKγ), whereas oxidized RhoGDI did not bind to IKKγ. The oxRhoA-GTP bound to IKKγ activated IKKβ, leading to IκB phosphorylation and degradation, consequently NF-κB activation. Hydrogen peroxide induced cell proliferation, but RhoA C16/20A mutant suppressed cell proliferation and tumorigenesis. Conclusively, RhoA oxidation at Cys16/20 is critically involved in cell proliferation and tumorigenesis through NF-κB activation in response to ROS.
authors.affiliation: Department of Biochemistry, Hallym University College of Medicine, Chuncheon, Kangwon-do 24252, Republic of Korea.
authors.forename: Jae-Gyu
authors.initials: JG
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Hallym University College of Medicine, Chuncheon, Kangwon-do 24252, Republic of Korea; Center for Medical Science Research, Hallym University College of Medicine, Chuncheon, Kangwon-do 24252, Republic of Korea.
authors.forename: Hyung-Joo
authors.initials: HJ
authors.lastname: Kwon
authors.affiliation: Center for Medical Science Research, Hallym University College of Medicine, Chuncheon, Kangwon-do 24252, Republic of Korea.
authors.forename: Guang
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Hallym University College of Medicine, Chuncheon, Kangwon-do 24252, Republic of Korea.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Park
authors.affiliation: Department of Biochemistry, Hallym University College of Medicine, Chuncheon, Kangwon-do 24252, Republic of Korea; Institute of Cell Differentiation and Ageing, Hallym University College of Medicine, Chuncheon, Kangwon-do 24252, Republic of Korea.
authors.forename: Jae-Yong
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Hallym University College of Medicine, Chuncheon, Kangwon-do 24252, Republic of Korea; Institute of Cell Differentiation and Ageing, Hallym University College of Medicine, Chuncheon, Kangwon-do 24252, Republic of Korea.
authors.forename: Jaebong
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Hallym University College of Medicine, Chuncheon, Kangwon-do 24252, Republic of Korea; Institute of Cell Differentiation and Ageing, Hallym University College of Medicine, Chuncheon, Kangwon-do 24252, Republic of Korea.
authors.forename: Sung-Chan
authors.initials: SC
authors.lastname: Kim
authors.affiliation: Department of Bio-Health and Technology, School of Biomedical Science and Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon, Kangwon-do 24341, Republic of Korea.
authors.forename: Myoen
authors.initials: M
authors.lastname: Choe
authors.affiliation: Division of Biomedical Convergence, School of Biomedical Science and Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon, Kangwon-do 24341, Republic of Korea.
authors.forename: Seung Goo
authors.initials: SG
authors.lastname: Kang
authors.affiliation: Department of Molecular Bioscience, School of Biomedical Science and Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon, Kangwon-do 24341, Republic of Korea.
authors.forename: Goo-Young
authors.initials: GY
authors.lastname: Seo
authors.affiliation: Department of Molecular Bioscience, School of Biomedical Science and Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon, Kangwon-do 24341, Republic of Korea.
authors.forename: Pyeung-Hyeun
authors.initials: PH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Hallym University College of Medicine, Chuncheon, Kangwon-do 24252, Republic of Korea; Center for Medical Science Research, Hallym University College of Medicine, Chuncheon, Kangwon-do 24252, Republic of Korea; Institute of Cell Differentiation and Ageing, Hallym University College of Medicine, Chuncheon, Kangwon-do 24252, Republic of Korea. Electronic address: jbpark@hallym.ac.kr.
authors.forename: Jae-Bong
authors.initials: JB
authors.lastname: Park
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D005260:Female; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051550:I-kappa B Kinase / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010084:Oxidation-Reduction; D011485:Protein Binding; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D000067996:RAW 264.7 Cells; D015398:Signal Transduction; D047368:Tumor Burden; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D016328:NF-kappa B; D051567:Proto-Oncogene Proteins c-vav; C490565:Vav2 protein, mouse; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D006861:Hydrogen Peroxide; D051550:I-kappa B Kinase; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
keywords: Cell proliferation; NF-κB; Oxidation; RhoA; Tumor