Hepatocyte growth factor signal coupling to various transcription factors depends on triggering of Met receptor and protein kinase transducers in human hepatoma cells HepG2.
Hepatocyte growth factor (HGF) regulates a wide variety of biological activities by binding to the tyrosine kinase receptor Met. In HGF-treated hepatocarcinoma cells, we observed a biphasic activation of AP-1 and AP-2 transcription factors. For NF-kappaB complex the p50-p50 homodimer was activated before the p50-p65 heterodimer, and c-Myc/Max DNA-binding activity increased thereafter. Since these transcription factors are responders to mitogenic stimulation through protein kinase transducers, we tested the effects of inhibitors of these enzymes on the DNA binding after HGF treatment. Inhibition of protein kinase C (PKC) with H7 strikingly activated NF-kappaB above the values observed after HGF alone. Under this inhibitory condition, Met tyrosine phosphorylation was elevated as though the phosphorylation-dependent activity of the receptor was partially blocked by activation of PKC due to HGF. NF-kappaB DNA binding seems to be related to Met triggering by HGF since it was largely prevented by genistein treatment, which blocks receptor activity. Phosphatidylinositol 3-kinase seems to be involved in AP-1 binding activity stimulated by HGF. It is noteworthy that Met is responsive to HGF stimulating postreceptor signaling, which converges on the activation of transcription factors acting coordinately to regulate target gene expression.
Tacchini
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Institute of General Pathology and C. N. R. Center for Research on Cell Pathology, University of Milano, Via L. Mangiagalli, Milano, 31-20133, Italy.
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Matteucci
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D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D006528:Carcinoma, Hepatocellular; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C499330:MAX protein, human; C067850:Myc associated factor X; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D019000:Phosphotyrosine; D017228:Hepatocyte Growth Factor; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met; D011493:Protein Kinase C