Activation of parallel mitogen-activated protein kinase cascades and induction of c-fos by cadmium

Cadmium is a toxic divalent cation that can initiate either mitogenic signals or apoptosis, possibly as a consequence of inducing different patterns of oncogene expression in different cells. We previously showed that Cd(2+) caused transcriptional activation of the c-fos protooncogene in mesangial cells (Wang and Templeton, J. Biol. Chem. 273, 73-79, 1998). The present study was undertaken to identify the signaling pathways that might be involved. Exposure to 10 microM CdCl(2) for 8 h caused a prolonged activation of Erk kinase and accumulation of c-fos mRNA. Inhibition of Erk activation with PD98059 only partially inhibited c-fos induction, indicating that additional pathways are involved. The c-Jun kinase/stress-activated protein kinase (SAPK) was also activated by Cd(2+). All three signals, i.e., Erk activity, SAPK activity, and c-fos mRNA levels in response to Cd(2+) showed a similar biphasic time course with an initial increase at 15-30 min and then a larger and more prolonged increase several hours later. Each signal also showed a similar concentration dependence, with less than 1 microM Cd(2+) causing the initial increase but values above 3 microM being required for the prolonged phase. These events showed high specificity for Cd(2+); other divalent metals tested under the same conditions (Mg(2+), Mn(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), and Hg(2+)) were without significant effects. We conclude that Cd(2+) is a specific inducer of c-fos in mesangial cells, probably through activation of both Erk kinase and SAPK pathways. The similar time and concentration dependence of the response of both pathways to Cd(2+) suggests a common basis for activation.