Hepatocyte growth factor-induced expression of ornithine decarboxylase, c-met, and c-myc is differently affected by protein kinase inhibitors in human hepatoma cells HepG2.
Binding of hepatocyte growth factor (HGF) to its receptor Met induces autophosphorylation and activation of the tyrosine kinase activity. In HGF-treated HepG2 cells, we studied: (i) the expression patterns of early (c-myc, c-jun, and c-fos) and delayed-early (ornithine decarboxylase and c-met) response genes and (ii) the possible involvement of protein kinase transducers in the control of the expression of c-met and of other genes eventually induced downstream. c-met and c-myc mRNAs peaked 1-2 h after HGF, while c-jun and c-fos mRNAs slightly increased at 1 h. Ornithine decarboxylase activity was induced earlier (4 h) than the mRNA (8-10 h). The transducers involved in HGF-triggered gene inductions were investigated using different protein kinase inhibitors: genistein for the receptor tyrosine kinase, herbimycin A for the nonreceptor tyrosine kinase (pp60(c-src)), wortmannin for phosphatidylinositol 3-kinase (PI3K) and H7 for protein kinase C (PKC). The similarity of responses to PKC inhibition led to suppose that c-myc and ornithine decarboxylase mRNAs were induced sequentially along the same transduction pathway triggered by HGF. Ornithine decarboxylase activity seemed to be largely regulated by phosphorylation(s). The mRNA expression of c-jun was likely to undergo a negative regulation through a mechanism involving PI3K, while that of c-met seemed to be almost independent from various protein kinases (PI3K, pp60(c-src), and PKC).
Institute of General Pathology and CNR Center for Research on Cell Pathology, University of Milano, via Mangiagalli, Milan, 31-20133, Italy. desi@imiucca.csi.unimi.it
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D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D009955:Ornithine Decarboxylase / Q000187:drug effects* / Q000235:genetics; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun / Q000187:drug effects / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000187:drug effects* / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000187:drug effects* / Q000235:genetics; D011519:Proto-Oncogenes / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism
D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor; D004247:DNA; D019859:Proto-Oncogene Proteins c-met; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D009955:Ornithine Decarboxylase