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 Ras and Raf proteins. This study demonstrates a direct correlation between Ras transforming activity and c-Jun activation, supporting an important role for c-Jun in transformation by Ras. Since we observed that Ras activated c-Jun transcriptional activity by increasing phosphorylation of the c-Jun activation domain at residues Ser-63/Ser-73 and that oncogenic Ras proteins activated extracellular signal-regulated protein kinases (ERK1 and ERK2) (also known as mitogen-activated protein kinases), we evaluated the possibility that ERKs were directly responsible for c-Jun activation. Coexpression of wild-type ERKs with oncogenic Ras proteins potentiated, while kinase-defective ERKs inhibited, Ras-induced transcriptional activation from the Ras-responsive element (Ets-1/AP-1) present in the NVL-3 enhancer and the serum-response element in the c-fos promoter. In contrast, coexpression of either wild-type or kinase-defective ERKs inhibited Ras and Raf activation of c-Jun transcriptional activity. Thus, although activation of both ERK and c-Jun are downstream consequences of activation of the Ras signal transduction pathway, our results suggest that Ras-induced c-Jun phosphorylation and transcriptional activation are not a direct consequence of ERK1 and ERK2 activation.
Westwick
J K
JK
Department of Medicine, University of North Carolina, Chapel Hill 27599.
Cox
A D
AD
Der
C J
CJ
Cobb
M H
MH
Hibi
M
M
Karin
M
M
Brenner
D A
DA
D016475:3T3 Cells; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002461:Cell Line, Transformed; D016762:Genes, fos; D011905:Genes, ras; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D010748:Phosphopeptides / Q000302:isolation & purification / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
D010748:Phosphopeptides; D016755:Proto-Oncogene Proteins c-jun; D008156:Luciferases; D005982:Glutathione Transferase; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D015689:Oncogene Protein p21(ras)