ONCOGENIC RAS ACTIVATES C-JUN VIA A SEPARATE PATHWAY FROM THE ACTIVATION OF EXTRACELLULAR SIGNAL-REGULATED KINASES

c-Jun transcriptional activity is augmented by expression of oncogenic Res and Raf proteins. This study demonstrates a direct correlation be tween Ras transforming activity and c-Jun activation, supporting an im portant role for c-Jun in transformation by Ras. Since we observed tha t Ras activated c-Jun transcriptional activity by increasing phosphory lation of the c-Jun activation domain at residues Ser-63/Ser-73 and th at oncogenic Ras proteins activated extracellular signal-regulated pro tein kinases (ERK1 and ERK2) (also known as mitogen-activated protein kinases), we evaluated the possibility that ERKs were directly respons ible for c-Jun activation. Coexpression of wild-type ERKs with oncogen ic Ras proteins potentiated, while kinase-defective ERKs inhibited, Ra s-induced transcriptional activation from the Ras-responsive element ( Ets-1/AP-1) present in the NVL-3 enhancer and the serum-response eleme nt in the c-fos promoter. In contrast, coexpression of either wild-typ e or kinase-defective ERKs inhibited Ras and Raf activation of c-Jun t ranscriptional activity. Thus, although activation of both ERK and c-J un are downstream consequences of activation of the Ras signal transdu ction pathway, our results suggest that Ras-induced c-Jun phosphorylat ion and transcriptional activation are not a direct consequence of ERK 1 and ERK2 activation.