Ras/MAP kinase-dependent and -independent signaling pathways target distinct ternary complex factors.
Transcriptional activation of the immediate early genes c-fos and egr-1 by extracellular signals appears to be mediated by ternary complex factors (TCFs). In BAC-1 macrophages, growth factor stimulation leads to the retardation of protein-DNA complexes containing distinct TCFs. One TCF is recognized by Elk-1 antisera, whereas the other is immunologically related to SAP-1. The appearance and decay of hyperphosphorylated TCF/Elk-1-containing complexes after stimulation coincide with the activation of mitogen-activated protein kinase (MAPK) and the induction and repression of c-fos and egr-1, whereas modified TCF/SAP-1-containing complexes decay more slowly. Suppression of MAPK activation in macrophages and fibroblasts correlates with the failure to induce TCF/Elk-1 hyperphosphorylation without blocking TCF/SAP-1 modification. Accordingly the modified Elk-1 complex is generated in vitro by activated MAPK, whereas that of SAP-1 is not. Expression of a dominant-negative Ras mutant (RasAsn17) in BAC-1 cells does not affect CSF-1-induced TCF/SAP-1 modification while suppressing TCF/Elk-1 phosphorylation. Neither PKC down-regulation by TPA nor inhibition of Gi proteins by pertussis toxin pretreatment influences CSF-1-induced signaling to TCFs. These data indicate the existence of two separate signaling pathways for the modification of distinct TCFs: one dependent on Ras and MAPK and converging on TCF/Elk-1, and the other targeting TCF/SAP-1 independently of Ras and MAPK.
Institute for Molecular Biology, Hannover Medical School, Germany.
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Hipskind
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Büscher
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Nordheim
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Baccarini
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000502:physiology*; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D017781:Genes, Immediate-Early / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D008934:Mitogens; D008969:Molecular Sequence Data; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D012045:Regulatory Sequences, Nucleic Acid; D015682:Retroviridae Proteins, Oncogenic / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D050808:ets-Domain Protein Elk-4; D018631:ras Proteins / Q000502:physiology*
D004268:DNA-Binding Proteins; C494112:ELK1 protein, human; C494193:ELK4 protein, human; C494113:Elk1 protein, mouse; C494194:Elk4 protein, mouse; D008934:Mitogens; D011518:Proto-Oncogene Proteins; D015682:Retroviridae Proteins, Oncogenic; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D050808:ets-Domain Protein Elk-4; D016173:Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins