Proto-oncogene Ras GTPase-linked induction of glutathione-S-transferase bygrowth factors in PC12 cells

This report provides evidence linking activation of Ras GTPase by growth fa ctors and induction of glutathione-S-transferase isozymes in PC12 cells. Ra s GTPase was activated by EGF, NGF, insulin and phorbolester in PC12 cells. Activation of Ras GTPase was found to be associated with induction of the expression of GST mu and pi isoenzymes while there was no detectable induct ion of GST alpha expression. GST pi was found to be induced by all the Ras GTPase activating agents tested while activation of Ras by phorbolester and insulin induced expression of GST mu only. These results suggest a role of Ras, at least in part, in controlling the expression of GST and that there might be independent signalling pathways for the expression of different G ST isoenzymes. GST activity was found to be very high (4-fold) in the lysat e obtained from retinoic acid treated PC12 cells when compared with untreat ed cells. Induction of GST expression was found to be initiated within 30 m in of retinoic acid treatment in PC12 cells reaching a maximum level at 4 h . However, immunoblot analysis showed that retinoic acid (RA), unlike mitog ens/growth factors, weakly induced the expression of GST pi but not the exp ression of alpha, mu and microsomal GSTs. Overxpression of inhibitory polyp eptides that block signals generated from Ras and Cdc42 was found to revers e the retinoic acid activation-dependent induction of GST expression in PC1 2 cells. These results provide evidence for the first time suggesting a nov el role of Ras GTPase in the regulation of GST expression which might have a significant implication in developing drug resistance and/or growth of ca ncer cells.