Regulation of normal cell cycle progression by flavin-containing oxidases
| Autor: | S. M. de Toledo, Perumal Venkatachalam, A. B. Carter, Douglas R. Spitz, Linda A. Tephly, Edouard I. Azzam, John B. Little, B N Pandey |
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| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
Cell cycle checkpoint Cell Survival Flavoprotein Biology Cell Line Membrane Potentials Mitochondrial Proteins Mice Onium Compounds Flavins Genetics Animals Humans Molecular Biology Cells Cultured Mice Inbred C3H Oxidase test Cell growth Kinase Cell Cycle NADPH Oxidases Fibroblasts Cell cycle Growth Inhibitors Cell biology Nitric oxide synthase biology.protein NAD+ kinase Oxidation-Reduction Signal Transduction |
| Zdroj: | Oncogene. 27:20-31 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/sj.onc.1210634 |
| Popis: | Mechanisms underlying the role of reactive oxygen species (ROS) generated by flavin-containing oxidases in regulating cell cycle progression were examined in human and rodent fibroblasts. Incubation of confluent cell cultures with nontoxic/nonclastogenic concentrations of the flavoprotein inhibitor, diphenyleneiodonium (DPI), reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase activity and basal ROS levels, but increased proteolysis of cyclin D1, p21(Waf1) and phospho-p38(MAPK). When these cells were allowed to proliferate by subculture in DPI-free medium, an extensive G(1) delay was observed with concomitant activation of p53/p21(Waf1) signaling and reduced phosphorylation of mitogen-activated kinases. Compensation for decreased oxidant generation by simultaneous exposure to DPI and nontoxic doses of the ROS generators, gamma-radiation or t-butyl-hydroperoxide, attenuated the G(1) delay. Whereas the DPI-induced G(1) checkpoint was completely dependent on PHOX91, ATM and WAF1, it was only partially dependent on P53. Interestingly, G(1) to S progression was not affected when another flavin-containing enzyme, nitric oxide synthase, was inhibited nor was it associated with changes in mitochondrial membrane potential. Proliferating cells treated with DPI also experienced a significant but attenuated delay in G(2). We propose that ATM performs a critical function in mediating normal cellular proliferation that is regulated by nonphagocytic NAD(P)H oxidase enzymes activity, which may serve as a novel target for arresting cancer cells in G(1). |
| Databáze: | OpenAIRE |
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