TYROSINE KINASE INHIBITORS POTENTIATE THE INDUCTION OF LOW-DENSITY-LIPOPROTEIN RECEPTOR GENE-EXPRESSION BY HEPATOCYTE GROWTH-FACTOR

The role of tyrosine kinase, protein kinase C, cyclic nucleotide- and Ca2+-calmodulin-dependent protein kinase second messenger pathways in the induction of LDL receptor gene expression by hepatocyte growth fac tor (HGF) was studied in the human hepatoma cell line Hep-G2. Incubati on with media containing HGF increased the level of LDL receptor mRNA by 6.5-fold. Co-incubation with HGF and either of two tyrosine kinase inhibitors genistein (2.0-20.0 mu g/ml) and herbimycin A (0.5-500.0 ng /ml) increased the level of LDL receptor mRNA above that observed with HGF alone by 40-60%. Incubation with HGF in the presence of the calmo dulin antagonist W7 (10-30 mu M) also super-induced the level of LDL r eceptor mRNA by nearly 230%. The protein kinase C and A inhibitors che lerythrine (0.1-10.0 mu M) and H8 (0.5-5.0 mu M), respectively, had no significant effects on the induction of LDL receptor mRNA by HGF. Tak en together, these data suggest that tyrosine kinase, protein kinases C and A, and Ca2+-calmodulin dependent protein kinase activities are n ot essential for activation of LDL receptor gene expression in Hep-G2 cells by HGF.