Oncogenic Ras Activates c-Jun Via a Separate Pathway from the Activation of Extracellular Signal-Regulated Kinases

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 91; no. 13; pp. 6030 - 6034
• Main Authors: Westwick, John K., Cox, Adrienne D., Der, Channing J., Cobb, Melanie H., Hibi, Masahiko, Karin, Michael, Brenner, David A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 21.06.1994; National Acad Sciences; National Academy of Sciences
• Subjects: 3T3 Cells; Animals; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell Line, Transformed; Cellular biology; DNA; Genes, fos; Genes, ras; Genetic vectors; Glutathione Transferase - biosynthesis; Glutathione Transferase - metabolism; Humans; Luciferases - biosynthesis; Luciferases - metabolism; Medical research; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; NIH 3T3 cells; Oncogene Protein p21(ras) - metabolism; Phosphopeptides - isolation & purification; Phosphopeptides - metabolism; Phosphorylation; Promoter Regions, Genetic; Proteins; Proto-Oncogene Proteins c-jun - biosynthesis; Proto-Oncogene Proteins c-jun - metabolism; Reporter genes; Signal Transduction; Transcription factors; Transfection
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.13.6030

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.