Induction of c-fos proto-oncogene in mesangial cells by cadmium.
Cadmium is mitogenic under some circumstances and has been shown to cause accumulation of transcripts for several proto-oncogenes in a variety of cells, but the mechanism(s) remain to be delineated. Here we show that CdCl2 causes an increase in c-fos mRNA within 30 min of exposure of mesangial cells. At 10 microM Cd2+, this increase persists for at least 8 h in both rat and human cells. The half-life of c-fos mRNA is the same whether it accumulates following 4 h of treatment with Cd2+ or is induced transiently by phorbol ester. Cycloheximide, which stabilizes the transcript, causes a synergistic increase when administered with CdCl2. Nuclear run-on analysis confirms that Cd2+ causes transcriptional activation of the c-fos gene. Calmodulin and Ca2+/calmodulin-dependent kinase, and classical protein kinase C (PKC) isoforms represent two Ca2+-dependent signaling pathways that can lead to induction of c-fos, and Cd2+ has been shown to activate both calmodulin and PKC in vitro, possibly by virtue of the similar ionic radii of Cd2+ and Ca2+. Therefore, we investigated the effect of Cd2+ on these pathways in vivo. 10 microM CdCl2 did not increase total PKC activity or Ca2+/calmodulin-dependent kinase II activity and inhibited the latter at higher concentrations, ruling out either pathway in the Cd2+-dependent induction of c-fos. However, Cd2+ did lead to a sustained activation of the Erk family mitogen-activated protein kinases (MAPK) that correlated with induction of c-fos. A specific inhibitor of the MAPK kinases, PD98059, partially inhibited the induction of c-fos by Cd2+. We conclude that Cd2+ induces c-fos at least in part by causing a sustained activation of MAPK independent of its ability to activate PKC and calmodulin in vitro.
Wang
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Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1L5 Canada.
Templeton
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DM
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D019256:Cadmium Chloride / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects*; D016762:Genes, fos; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D011493:Protein Kinase C / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D051381:Rats; D015398:Signal Transduction
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019256:Cadmium Chloride; D002118:Calcium