title: Sodium arsenite-induced dysregulation of proteins involved in proliferative signaling.
abstract: It is well accepted that arsenic is a human carcinogen, yet its mechanism of action is not defined. Arsenic cannot be classified as an initiating agent or as a promoter, although altered proliferative responsiveness has been proposed as a mechanism by which arsenic exerts its carcinogenic effects. Based on the hypothesis that arsenic exposure results in modulation of both positive and negative regulators of cell proliferation, this study examined physiological and biochemical changes in the proliferative response of murine fibroblasts grown long-term in the maximum tolerated concentration of sodium arsenite. In response to EGF stimulation, DNA synthesis and the proportion of cells entering S phase of the cell cycle both were increased in cells grown long-term in arsenic compared to control cells. Analysis of positive proliferative regulators revealed an increase in the expression of c-myc and E2F-1, thereby supporting the hypothesis that arsenic increases activity of positive growth modulators. In contrast, the activity and expression of ERK-2 were unchanged, as was the expression of EGF-receptor and mSOS. When negative regulators of proliferation were examined, expression levels of MAP kinase phosphatase-1 and p27(Kip1) were found to be lower in arsenic-treated cells compared to control cells; this result supports a model in which arsenic disinhibits normal regulation of cell proliferation. Taken together, these data indicate that long-term exposure to sodium arsenite creates conditions within the cell consistent with sensitization to mitogenic stimulation. It is further postulated that the observed changes in mitogenic signaling proteins contribute to the carcinogenic property of arsenic.
authors.affiliation: Department of Pharmacology and Center for Environmental Toxicology, University of Nebraska Medical Center, Omaha, Nebraska, 68198-6260, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Trouba
authors.forename: E M
authors.initials: EM
authors.lastname: Wauson
authors.forename: R L
authors.initials: RL
authors.lastname: Vorce
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D004815:Epidermal Growth Factor / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects*; D016271:Proto-Oncogene Proteins c-myc / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D017670:Sodium Compounds / Q000633:toxicity*
chemical_list: D018053:Arsenites; D004791:Enzyme Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D017670:Sodium Compounds; C017947:sodium arsenite; D004815:Epidermal Growth Factor; D004247:DNA; D020929:Mitogen-Activated Protein Kinase Kinases