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 mu M 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+ h, been shown to activate both calmodulin and PRC 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 mu M CdCl2 did not increase total PRC 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.