Cd(2+)-induced c-myc mRNA accumulation in NRK-49F cells is blocked by the protein kinase inhibitor H7 but not by HA1004, indicating that protein kinase C is a mediator of the response.

Cd2+ is a toxic cation that, at sublethal and marginally lethal levels, modifies cell growth and metabolism. Cd2+ exposure of NRK-49F cells results in inhibition of early EGF-induced DNA synthesis, but induction of delayed DNA synthesis; in stimulation of anchorage independent growth; in accumulation of specific oncogene mRNAs; and in an hypertrophic response. Determining whether specific signal transduction pathways (STPs) are involved in specific gene deregulation by cadmium in NRK-49F cells is important to defining possible mechanisms by which Cd2+ elicits these physiological responses. In this study it is shown that Cd2+ induces delayed myc (8-10 h) and jun (12 h) mRNA accumulation, as well as both early (0.5-1 h) and late (12 h) fos but not TGF beta mRNA accumulation. The times of appearance of Cd(2+)-induced c-fos, c-myc and c-jun expression are dose dependent. The Cd2+ induced accumulation of these specific mRNAs is insensitive to cycloheximide and therefore not due to preinduction of TGF beta or other gene-activating growth factors, but rather to direct induction of oncogene expression and/or mRNA stabilization. Accumulation of c-myc mRNA is shown further to be inhibited by the protein kinase inhibitor H7 but not HA1004, indicating a role for one or more protein kinases C in the STPs by which Cd2+ induces oncogene expression. Thapsigargin, a compound which stimulates increased cytosolic [Ca2+], induces c-myc expression also by an H7 sensitive, HA1004 insensitive pathway. These results suggest that Cd2+ acts through one or more defined signal transduction pathways involving specific protein kinases C to induce the accumulation of c-fos, c-myc and c-jun messenger RNAs.