DIFFERENTIAL ACTIVATION OF P38 MITOGEN-ACTIVATED PROTEIN-KINASE AND EXTRACELLULAR SIGNAL-REGULATED PROTEIN-KINASES CONFERS CADMIUM-INDUCED HSP70 EXPRESSION IN 9L RAT-BRAIN TUMOR-CELLS

We have reported that treatment with CdCl2 at 40-100 mu M induces the heat shock proteins (HSPs) in 9L rat brain tumor cells, during which t he activation of heat shock factor (HSF) is essentially involved. By e xploiting protein kinase inhibitors, we further analyzed the possible participation of specific protein kinases in the above processes. It w as found that induction of HSP70 in cells treated with a high concentr ation of cadmium (i.e. 100 mu M) is preceded by the phosphorylation an d activation of p38 mitogen-activated protein kinase (p38(MAPK)), whil e that in cells treated with a low concentration (60 mu M) is accompan ied by the phosphorylation and activation of extracellular-regulated p rotein kinases 1 and 2 (ERK1/2). In 100 mu M cadmium-treated cells, bo th HSP70 induction and HSF1 activation are eliminated in the presence of SB203580, a specific inhibitor of p38(MAPK). By contrast, in 60 mu M cadmium-treated cells, the processes are not affected by SB203580 bu t are significantly suppressed by PD98059, which indirectly inhibits E RK1/2 by acting on MAPK-ERK kinase. Taken together, we demonstrate tha t p38(MAPK) and ERK1/2 can be simultaneously or independently activate d under different concentrations of cadmium and that the signaling pat hways participate in the induction of HSP70 by acting on the inducible phosphorylation of HSF1. We thus provide the first evidence that both p38(MAPK) and ERK signaling pathways can differentially participate i n the activation of HSF1, which leads to the induction of HSP70 by cad mium.