Elevated ERK-MAP kinase activity protects the FOS family member FRA-1 against proteasomal degradation in colon carcinoma cells.
The AP-1 (activator protein-1) complex, which consists of proteins of the Fos and Jun families, is thought to play an important role in the balance between cell proliferation and apoptosis, the response to genotoxic stress and cell transformation. In cells containing oncogenic Ras, the major components of AP-1 are Fra-1 and c-Jun. Signalling from Ras to AP-1 is through the Raf/MEK[mitogen-activated protein (MAP) kinase kinase]/ERK (extracellular signal-regulated kinase) MAP kinase pathway as sustained activation of Raf1 or Mek1 modifies AP-1 composition and activity. To analyse the potential link between the ERK-MAPK pathway and AP-1 in colon cancer, in which RAS and BRAF mutations are frequent, we have studied the regulation of AP-1 in colon carcinoma cell lines. We show that c-JUN and FRA-1 expression is dependent on ERK activity and that different thresholds of ERK activity control the expression of FRA-1. A basal activity is required to induce transcription of the FRA-1 gene, but additional higher levels of activity stabilize FRA-1 against proteasome-dependent degradation. These results provide a clear-cut example that the magnitude of ERK signalling affects the cellular response. Although we find no contribution of FRA-1 towards cell proliferation of adherent tumour cells, the high levels of FRA-1 in cells where elevated ERK activity leads to protein stabilization provide survival signals for tumour cells removed from the extracellular matrix.
Vial
Emmanuel
E
Cancer Research UK Centre for Cell and Molecular Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
Marshall
Christopher J
CJ
D002470:Cell Survival; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism*; D009154:Mutation; D046988:Proteasome Endopeptidase Complex; D011489:Protein Denaturation / Q000502:physiology*; D048493:Proto-Oncogene Proteins B-raf; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D000099169:Fos-Related Antigen 1
D003546:Cysteine Endopeptidases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D009097:Multienzyme Complexes; D046988:Proteasome Endopeptidase Complex; D048493:Proto-Oncogene Proteins B-raf; D016760:Proto-Oncogene Proteins c-fos; D019908:Proto-Oncogene Proteins c-raf; D018808:Transcription Factor AP-1; D000099169:Fos-Related Antigen 1; C482119:BRAF protein, human