title: ATM/ATR-related checkpoint signals mediate arsenite-induced G2/M arrest in primary aortic endothelial cells.
abstract: Epidemiological studies have demonstrated a high association of inorganic arsenic exposure with vascular disease. Our recent in vitro studies have linked this vascular damage to vascular endothelial dysfunction induced by arsenic exposure. However, cell-cycle arrest induced by arsenic and its involvement in vascular dysfunction remain to be clarified. In this study, we employed primary porcine aortic endothelial cells to investigate regulatory mechanisms of G2/M phase arrest induced by arsenite. Our study revealed that lower concentrations of arsenite (1 and 3 microM) increased cell proliferation, whereas higher concentrations of arsenite (10, 20, and 30 microM) inhibited cell proliferation together with correlated increases in G2/M phase arrest. We found that this arsenite-induced G2/M phase arrest was accompanied by accumulation and/or phosphorylation of checkpoint-related molecules, including p53, Cdc25B, Cdc25C, and securin. Inhibition of activations of these checkpoint-related molecules by caffeine significantly attenuated the 30-microM arsenite-induced G2/M phase arrest by 93%. Our data suggest that the DNA damage responsive kinases ATM (ataxia-telangiectasia mutated) and ATR (ATM and Rad3-related) play critical roles in arsenite-induced G2/M phase arrest in aortic endothelial cells possibly via regulation of checkpoint-related signaling molecules including p53, Cdc25B, Cdc25C, and securin.
authors.affiliation: Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan. tctsou@nhri.org.tw
authors.forename: Tsui-Chun
authors.initials: TC
authors.lastname: Tsou
authors.forename: Feng-Yuan
authors.initials: FY
authors.lastname: Tsai
authors.forename: Szu-Ching
authors.initials: SC
authors.lastname: Yeh
authors.forename: Louis W
authors.initials: LW
authors.lastname: Chang
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018053:Arsenites / Q000633:toxicity*; D064007:Ataxia Telangiectasia Mutated Proteins; D002110:Caffeine / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D016195:G2 Phase / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017670:Sodium Compounds / Q000633:toxicity*; D013552:Swine; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: D018053:Arsenites; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047428:Protein Kinase Inhibitors; D017670:Sodium Compounds; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D002110:Caffeine; C017947:sodium arsenite; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D020687:cdc25 Phosphatases