Cadmium and calcium-dependent c-fos expression in mesangial cells.
Cadmium is a carcinogenic metal known to increase the expression of several protooncogenes in a variety of cells. although the underlying mechanisms are unknown. Renal mesangial cells are smooth muscle cells in which Ca2+ signaling pathways regulate the induction of c-fos through both cAMP-dependent and mitogen-activated protein kinase- (MAPK-) dependent pathways. We report that c-fos is induced in these cells by both protein kinase C- (PKC-) dependent (phorbol ester, platelet-derived growth factor), and independent (serum, ionomycin) mechanisms. In all cases, prevention of an increase in cytosolic [Ca2+] with the chelator BAPTA prevented this induction. CdCl2 (10 microM) caused an accumulation of c-fos mRNA over 30 min that was sustained for at least 8 h. Cycloheximide inhibits turnover of c-fos mRNA and shows a synergistic effect with Cd2+ on transcript levels. Together with a similar half life of the transcript whether accumulated in response Cd2+ or induced by phorbol ester, this suggests induction of c-fos by Cd2+ rather than an effect of Cd2+ on transcript stability. Cadmium increased MAPK activity by 5 min; this was sustained for at least 8 h, consistent with the time course of c-fos mRNA accumulation. The MAPK kinase inhibitor PD98059 caused a marked decrease in the induction of c-fos by Cd2+, but did not eliminate the phenomenon completely. Although Cd2+ has been reported to activate PKC in vitro, no effect was found on PKC activity in Cd2+ -treated cells, indicating the activation of MAPK by Cd2+ is through an unidentified PKC-independent pathway. We conclude that Cd2+ can cause a sustained induction of c-fos in part through sustained activation of MAPK, that contrasts with the transient activation of these species in response to physiological mitogenic stimuli.
Templeton
D M
DM
Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada. doug.templeton@utoronto.ca
Wang
Z
Z
Miralem
T
T
D000818:Animals; D002104:Cadmium / Q000633:toxicity*; D002118:Calcium / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects*; D005920:Glomerular Mesangium / Q000187:drug effects*; D008297:Male; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D002104:Cadmium; D004533:Egtazic Acid; D000242:Cyclic AMP; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium