Reactive oxygen species (ROS: superoxide and hydrogen peroxide) produced as by products of oxidative energy metabolism have been shown to be important mediators of physiologic signaling processes. This proposal is designed to test the hypothesis that ROS (i.e., superoxide and hydrogen peroxide) regulate progression from G1 to S phase via redox regulation of G1 cell cycle regulatory proteins. This hypothesis is based on our observations that a pro-oxidant signal at the end of the G1 phase of the normal fibroblast cell cycle appears to be necessary for stimulation of entry into S-phase. Furthermore, we have shown over expression of antioxidant enzymes (phospholipid hydroperoxide glutathione peroxidase and Mn-superoxide dismutase) induce a G1-delay in human breast and prostate cancer cells. These observations suggest that redox regulation of the cell cycle could provide a mechanistic link between the cell cycle regulatory proteins and the oxidative metabolic processes necessary for the successful completion of each cell cycle phase.
Three specific aims are proposed to rigorously test the stated hypothesis:
Aim 1 : Determine if intracellular antioxidant enzymes that metabolize superoxide and hydrogen peroxide (MnSOD, CuZnSOD, catalase and/or glutathione peroxidase) modulate cell cycle progression from GI to S in nonmalignant mouse and human fibroblasts.
Aim 2 : Determine if steady-state levels of superoxide and hydrogen peroxide fluctuate as cells progress through the various phases of the cell cycle and if fluctuations in ROS between different phases of the cell cycle are mediated by changes in antioxidant enzyme expression.
Aim 3 : Determine if antioxidant enzyme mediated alterations in progression from GI to S are caused by changes in the redox regulation of cyclin D1 expression. A mechanistic evaluation of intracellular redox environment and cell cycle progression could lead to a better understanding of normal and aberrant cellular proliferation. Since proliferative disorders are central to a variety of human pathophysiological conditions including normal tissue injury as well as tumor cell response during cancer therapy, results obtained from completion of the studies in this proposal could provide a biochemical rationale for manipulating cell proliferation to improve outcome. ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Etiology Study Section (CE)
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Okano, Paul
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University of Iowa
Schools of Medicine
Iowa City
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Son, Jyung Mean; Sarsour, Ehab H; Kakkerla Balaraju, Anurag et al. (2017) Mitofusin 1 and optic atrophy 1 shift metabolism to mitochondrial respiration during aging. Aging Cell 16:1136-1145
Kalen, Amanda L; Ahmad, Iman M; Abdalla, Maher Y et al. (2017) MnSOD and Cyclin B1 Coordinate a Mito-Checkpoint during Cell Cycle Response to Oxidative Stress. Antioxidants (Basel) 6:
Mapuskar, Kranti A; Flippo, Kyle H; Schoenfeld, Joshua D et al. (2017) Mitochondrial Superoxide Increases Age-Associated Susceptibility of Human Dermal Fibroblasts to Radiation and Chemotherapy. Cancer Res 77:5054-5067
Xiao, Wusheng; Sarsour, Ehab H; Wagner, Brett A et al. (2016) Succinate dehydrogenase activity regulates PCB3-quinone-induced metabolic oxidative stress and toxicity in HaCaT human keratinocytes. Arch Toxicol 90:319-32
Mao, Gaowei; Goswami, Monali; Kalen, Amanda L et al. (2016) N-acetyl-L-cysteine increases MnSOD activity and enhances the recruitment of quiescent human fibroblasts to the proliferation cycle during wound healing. Mol Biol Rep 43:31-9
Du, Juan; Cieslak 3rd, John A; Welsh, Jessemae L et al. (2015) Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer. Cancer Res 75:3314-26
Cieslak, John A; Cullen, Joseph J (2015) Treatment of Pancreatic Cancer with Pharmacological Ascorbate. Curr Pharm Biotechnol 16:759-70
Xiao, Wusheng; Goswami, Prabhat C (2015) Down-regulation of peroxisome proliferator activated receptor ? coactivator 1? induces oxidative stress and toxicity of 1-(4-Chlorophenyl)-benzo-2,5-quinone in HaCaT human keratinocytes. Toxicol In Vitro 29:1332-8
Xiao, Wusheng; Son, Jyungmean; Vorrink, Sabine U et al. (2015) Ligand-independent activation of aryl hydrocarbon receptor signaling in PCB3-quinone treated HaCaT human keratinocytes. Toxicol Lett 233:258-66
Sibenaller, Zita A; Welsh, Jessemae L; Du, Changbin et al. (2014) Extracellular superoxide dismutase suppresses hypoxia-inducible factor-1? in pancreatic cancer. Free Radic Biol Med 69:357-66

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