Manganese superoxide dismutase activity regulates transitions between quiescent and proliferative growth

Summary 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 modu...

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Published in:Aging cell 2008-06, Vol.7 (3), p.405-417
Main Authors: Sarsour, Ehab H., Venkataraman, Sujatha, Kalen, Amanda L., Oberley, Larry W., Goswami, Prabhat C.
Format: Article
Language:English
Subjects:
antioxidant enzymes
cell cycle
Cell Proliferation
Cells, Cultured
Cyclin B - metabolism
Cyclin B1
cyclin D1
Cyclin D1 - metabolism
Fibroblasts - cytology
Fibroblasts - metabolism
Humans
hydrogen peroxide
Hydrogen Peroxide - analysis
MnSOD
Reactive Oxygen Species - analysis
Reactive Oxygen Species - metabolism
ROS
superoxide
Superoxide Dismutase - deficiency
Superoxide Dismutase - metabolism
Superoxides - analysis
Superoxides - metabolism
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Summary:Summary 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 G2 cells compared to MnSOD (+/+) MEFs. Overexpression of MnSOD in MnSOD (+/–) MEFs suppressed superoxide levels and G2 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.
ISSN:1474-9718
1474-9726
DOI:10.1111/j.1474-9726.2008.00384.x