title: Manganese superoxide dismutase activity regulates transitions between quiescent and proliferative growth.
abstract: In recent years, the intracellular reactive oxygen species (ROS) levels have gained increasing attention as a critical regulator of cellular proliferation. We investigated the hypothesis that manganese superoxide dismutase (MnSOD) activity regulates proliferative and quiescent growth by modulating cellular ROS levels. Decreasing MnSOD activity favored proliferation in mouse embryonic fibroblasts (MEF), while increasing MnSOD activity facilitated proliferating cells' transitions into quiescence. MnSOD +/- and -/- MEFs demonstrated increased superoxide steady-state levels; these fibroblasts failed to exit from the proliferative cycle, and showed increasing cyclin D1 and cyclin B1 protein levels. MnSOD +/- MEFs exhibited an increase in the percentage of G(2) cells compared to MnSOD +/+ MEFs. Overexpression of MnSOD in MnSOD +/- MEFs suppressed superoxide levels and G(2) accumulation, decreased cyclin B1 protein levels, and facilitated cells' transit into quiescence. While ROS are known to regulate differentiation and cell death pathways, both of which are irreversible processes, our results show MnSOD activity and, therefore, mitochondria-derived ROS levels regulate cellular proliferation and quiescence, which are reversible processes essential to prevent aberrant proliferation and subsequent exhaustion of normal cell proliferative capacity. These results support the hypothesis that MnSOD activity regulates a mitochondrial 'ROS-switch' favoring a superoxide-signaling regulating proliferation and a hydrogen peroxide-signaling supporting quiescence.
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Ehab H
authors.initials: EH
authors.lastname: Sarsour
authors.forename: Sujatha
authors.initials: S
authors.lastname: Venkataraman
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Kalen
authors.forename: Larry W
authors.initials: LW
authors.lastname: Oberley
authors.forename: Prabhat C
authors.initials: PC
authors.lastname: Goswami
mesh_terms: D049109:Cell Proliferation; D002478:Cells, Cultured; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D019938:Cyclin D1 / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000032:analysis; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism; D013482:Superoxide Dismutase / Q000172:deficiency / Q000378:metabolism*; D013481:Superoxides / Q000032:analysis / Q000378:metabolism
chemical_list: C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; D019926:Cyclin B; D056744:Cyclin B1; D017382:Reactive Oxygen Species; D013481:Superoxides; D019938:Cyclin D1; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase