CADMIUM AND CALCIUM-DEPENDENT C-FOS EXPRESSION IN MESANGIAL CELLS

Cadmium is a carcinogenic metal known to increase the expression of se veral protooncogenes in a variety of cells, although the underlying me chanisms are unknown. Penal 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-) dep endent pathways. We report that c-fos is induced in these cells by bot h 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 mu M) caused an accumulatio n of c-fos mRNA over 30 min that was sustained for at least 8 h. Cyclo heximide inhibits turnover of c-fos mRNA and shows a synergistic effec t with Cd2+ on transcript levels. Together with a similar half life of the transcript whether accumulated in response Cd2+ or induced by pho rbol ester, this suggests induction of c-fos by Cd2+ rather than an ef fect of Cd2+ on transcript stability. Cadmium,increased MAPK activity by, 5 min; this was sustained for at least 8 h, consistent with the ti me course of c-Sos mRNA accumulation. The MAPK kinase inhibitor PD9805 9 caused a marked decrease in the induction of c-fos by Cd2+, but did not eliminate the phenomenon completely. Although Cd2+ has been report ed to activate PKC in vitro; no effect was found on PKC activity in Cd 2+-treated cells, indicating the activation of MAPK by Cd2+ is through an unidentified PKC-independent pathway. We conclude that Cd2+ can ca use a sustained induction of c-fos in part through sustained activatio n of MAPK, that contrasts with the transient activation of these speci es in response to physiological mitogenic stimuli. (C) 1998 Elsevier S cience Ireland Ltd. All rights reserved.