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DIFFERENTIAL ACTIVATION OF AP-1 IN HUMAN BLADDER EPITHELIAL CELLS BY INORGANIC AND METHYLATED ARSENICALS
Drobna, Z., M Styblo, I. Jaspers, AND D J. Thomas. DIFFERENTIAL ACTIVATION OF AP-1 IN HUMAN BLADDER EPITHELIAL CELLS BY INORGANIC AND METHYLATED ARSENICALS. FASEB JOURNAL 17:67-69, (2003).
Differential Activation of AP-1 in Human Bladder Epithelial Cells by Inorganic and Methylated Arsenicals
Zuzana Drobna, Ilona Jaspers, David J. Thomas, and Miroslav Styblo
Epidemiological studies have linked chronic ingestion of drinking water containing inorganic arsenic (iAs) to increased incidences of various cancers, including cancer of urinary bladder. It has previously been suggested that mechanisms by which iAs promotes cancer include stimulation of activating protein-1 (AP-1) DNA binding through increased expression and/or phosphorylation of c-Jun and c-Fos, the constituents of AP-1. However, little is known about the effects of methylated arsenicals, metabolites of iAs, on AP-1 composition and activity. In this study, we show that short-term exposures to low concentrations (0.1 to 5 mM) of inorganic or methylated trivalent arsenicals, arsenite (iAsIII), methylarsine oxide (MAsIIIO), or iododimethylarsine (DMAsIIII), induces phosphorylation of c-Jun and increase AP-1 DNA binding activity in two human bladder epithelial cell lines, UROtsa and T24. DMAsIIII and especially MAsIIIO are considerably more potent than iAsIII as inducers of c-Jun phosphorylation and AP-1 activation in both cell lines. In contrast, exposures to either inorganic or methylated pentavalent arsenicals do not affect c-Jun phosphorylation. Phosphorylated c-Jun, JunB, and JunD, but not c-Fos or FosB, are detected in the AP-1 DNA binding complex in cells exposed to MAsIIIO or DMAsIIII. Hence, dimers composed of the Jun family proteins are likely the predominant forms of AP-1 in these cells. The potencies of MAsIIIO and DMAsIIII to activate AP-1 and to induce AP-1-dependent gene transcription in intact cells have also been examined using UROtsa and T24 cells transiently transfected with an AP-1-dependent promoter-reporter construct containing firefly luciferase cDNA. In this system, MAsIIIO is more potent than iAsIII in inducing the AP-1-depenedent luciferase activity. Thus, results of this work are consistent with the hypothesis that the biomethylation activates iAs and increases the toxicity and carcinogenic activity of this metalloid.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
EXPERIMENTAL TOXICOLOGY DIVISION