Differential activation of AP-1 in human bladder epithelial cells by inorganic and methylated arsenicals.
Chronic exposures to inorganic arsenic (iAs) have been linked to increased incidences of various cancers, including cancer of the urinary bladder. Mechanisms by which iAs promotes cancer may include stimulation of activator protein-1 (AP-1) DNA binding through increased expression and/or phosphorylation of the AP-1 constituents. However, the role of methylated metabolites of iAs in AP-1 activation has not been thoroughly examined. In this study, we show that short-time exposures to 0.1-5 microM arsenite (iAsIII) or the methylated trivalent arsenicals methylarsine oxide (MAsIIIO), or iododimethylarsine (DMAsIIII) induce phosphorylation of c-Jun and increase AP-1 DNA binding activity in human bladder epithelial cells. DMAsIIII and especially MAsIIIO are considerably more potent than iAsIII as inducers of c-Jun phosphorylation and AP-1 activation. Phosphorylated c-Jun, JunB, JunD, and Fra-1, but not c-Fos, FosB, or ATF-2, are detected in the AP-1-DNA binding complex in cells exposed to trivalent arsenicals. In cells transiently transfected with an AP-1-dependent promoter-reporter construct, MAsIIIO was more potent than iAsIII in inducing the AP-1-dependent gene transcription. Exposures to trivalent arsenicals induce phosphorylation of extracellular signal-regulated kinase (ERK), but not c-Jun N-terminal kinases or p38 kinases. These results indicate that an ERK-dependent signal transduction pathway is at least partially responsible for c-Jun phosphorylation and AP-1 activation in UROtsa cells exposed to inorganic or methylated trivalent arsenicals.
Drobná
Zuzana
Z
Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina 27599-7220, USA.
Jaspers
Ilona
I
Thomas
David J
DJ
Stýblo
Miroslav
M
D001152:Arsenicals / Q000494:pharmacology*; D018053:Arsenites / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D018808:Transcription Factor AP-1 / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation; D001743:Urinary Bladder / Q000166:cytology / Q000378:metabolism*
D001152:Arsenicals; D018053:Arsenites; D002273:Carcinogens; D004268:DNA-Binding Proteins; D018808:Transcription Factor AP-1; C062856:dimethylarsine; C080197:methylarsine oxide; D020928:Mitogen-Activated Protein Kinases