Reversible modulation of cell cycle kinetics in NIH/3T3 mouse fibroblasts by inducible overexpression of mitochondrial manganese superoxide dismutase.
To study the mechanism(s) by which manganese-containing superoxide dismutase (MnSOD) mediates cellular growth inhibition, an inducible retroviral vector system regulated by the lac repressor was used to overexpress MnSOD protein in NIH/3T3 cells. Increased MnSOD activity led to decreased cell growth due to prolonged cell cycle transition times in G(1) and S phases without significant changes in G(2)/M phase. Changes in cell cycle transition time were reversible and tightly correlated with MnSOD levels. A transient increase of reactive oxygen species and concomitant decrease in mitochondrial membrane potential were documented following MnSOD induction. N-Acetyl-L-cysteine prevented growth inhibition by MnSOD. Our data suggest that MnSOD may serve a physiological function of regulating cell cycle progression through its prooxidant activity of generating hydrogen peroxide, resulting in coordination of mitochondrial redox state and cellular proliferation.
Kim
Aekyong
A
Molecular and Environmental Toxicology Center, University of Wisconsin, Medical School, Madison, WI, USA.
Zhong
Weixiong
W
Oberley
Terry D
TD
D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle; D016923:Cell Death; D002455:Cell Division; D049109:Cell Proliferation; D005347:Fibroblasts / Q000201:enzymology*; D005470:Fluorometry; D016193:G1 Phase; D016195:G2 Phase; D005822:Genetic Vectors; D007150:Immunohistochemistry; D007544:Isopropyl Thiogalactoside / Q000494:pharmacology; D007700:Kinetics; D008564:Membrane Potentials; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D041681:NIH 3T3 Cells; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species; D012190:Retroviridae / Q000235:genetics; D016196:S Phase; D013482:Superoxide Dismutase / Q000235:genetics*; D013997:Time Factors; D014162:Transfection
D017382:Reactive Oxygen Species; D007544:Isopropyl Thiogalactoside; D013482:Superoxide Dismutase; D000111:Acetylcysteine