A G2/M growth arrest response to low-dose intermittent H2O2 in normal uroepithelial cells.
Studies in fibroblasts have shown that H2O2, as a model for oxidative damage, leads to a G1 growth arrest phenotypically similar to senescence. These observations as well as the observation that bladder cancer is associated with deletions of CDKN2, a gene important in normal senescence, led us to examine normal urothelial cell response to H2O2. We hypothesized that low dose H2O2 exposure would lead to p16 and/or p14arf mediated senescence. We show that H2O2 leads to endogenous beta-galactosidase expression similar to senescence, but instead of G1 arrest, it leads to G2/M growth arrest without induction of either p16 or p14arf. Lack of p21 induction and a similar G2/M growth arrest in E6 immortalized uroepithelial cells suggests that this response is independent of p53 as well. An increased level of cdc2 tyrosine-15 phosphorylation following H2O2 treatment suggests that the observed growth arrest is mediated by a G2 checkpoint mechanism.
Sections of Urology and Hematology/Oncology, Departments of Surgery and Medicine, Prostate Cancer Program, Cancer Research Center, University of Chicago, IL 60637, USA.
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Chien
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Rinker-Schaeffer
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Stadler
D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D016922:Cellular Senescence / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004334:Drug Administration Schedule; D016195:G2 Phase / Q000187:drug effects*; D017930:Genes, Reporter; D019942:Genes, p16; D006801:Humans; D006861:Hydrogen Peroxide / Q000008:administration & dosage / Q000494:pharmacology*; D008677:Metaphase / Q000187:drug effects*; D009687:Nuclear Proteins; D018384:Oxidative Stress; D027383:Papillomaviridae / Q000502:physiology; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051736:Proto-Oncogene Proteins c-mdm2; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D019459:Urothelium / Q000166:cytology / Q000187:drug effects*; D001616:beta-Galactosidase / Q000096:biosynthesis
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D018844:Cyclin-Dependent Kinases; D001616:beta-Galactosidase