Journal article
Regulation of normal cell cycle progression by flavin-containing oxidases
Oncogene, Vol.27(1), pp.20-31
01/03/2008
DOI: 10.1038/sj.onc.1210634
PMID: 17637756
Abstract
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 G1.
Details
- Title: Subtitle
- Regulation of normal cell cycle progression by flavin-containing oxidases
- Creators
- P. Venkatachalam - University of Medicine and Dentistry of New JerseySm de Toledo - University of Medicine and Dentistry of New JerseyBn Pandey - University of Medicine and Dentistry of New JerseyLa Tephly - Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Med, Iowa City, IA USAAb Carter - University of IowaJb Little - Harvard Univ, Sch Publ Hlth, Ctr Radiat Sci & Environm Hlth, Boston, MA 02115 USADr Spitz - Univ Iowa, Holden Comprehens Canc Ctr, Free Rad & Radiat Biol Program, Dept Radiat Oncol, Iowa City, IA USAEi Azzam - Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Radiol, Newark, NJ 07101 USA
- Resource Type
- Journal article
- Publication Details
- Oncogene, Vol.27(1), pp.20-31
- Publisher
- Springer Nature
- DOI
- 10.1038/sj.onc.1210634
- PMID
- 17637756
- ISSN
- 0950-9232
- eISSN
- 1476-5594
- Number of pages
- 12
- Grant note
- CA92262 / NCI NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01CA092262 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 01/03/2008
- Academic Unit
- Pathology; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984313075202771
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