Stress-activated protein kinase-dependent induction of c-fos by Cd2+ is mediated by MKK7

Exposure of mesangial cells to ionic Cd2+ induces the proto-oncogene c-fos, while activating both Erk and stress-activated protein kinase (SAPK) MAP k inase pathways. While we have previously used a pharmacological inhibitor o f Erk activation to implicate involvement of this pathway in the induction of c-fos by Cd2+, the consequences of SAPK activation remained unknown. Her e me use dominant negative inhibitors of the SAPK kinases, SEK1 and MKK7, t o show that Cd2+ activates SAPK through MKK7, but that partial inhibition o f SAPK alone is insufficient to significantly affect the magnitude of the C d2+-dependent increase in c-fos mRNA However, inhibition of Erk and SAPK pa thways together abrogates the increase, suggesting that these pathways act in concert in the induction of c-fos by this toxic metal. (C) 2000 Academic Press.