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Epidermal Growth Factor and Insulin-Induced Deoxyribonucleic Acid Synthesis in Primary Rat Hepatocytes Is Phosphatidylinositol 3-Kinase Dependent and Dissociated from Protooncogene Induction¹

Polypeptide Hormone Laboratory and the Departments of Medicine and Physiology, McGill University, Montréal, Québec, Canada

Address all correspondence and requests for reprints to: Dr. Barry I. Posner, Polypeptide Hormone Laboratory, Strathcona Medical Building, 3640 University Street, Room W315, Montréal, Québec, Canada H3A 2B2. E-mail: mc85{at}musica.mcgill.ca

The mitogenic response to insulin and epidermal growth factor (EGF) was studied in subconfluent and confluent cultures of primary rat hepatocytes. In subconfluent cultures, wortmannin, LY294002, and rapamycin reversed insulin- and EGF-induced [³H]thymidine incorporation into DNA. The mitogen-activated protein kinase (MAPK) kinase 1 (MEK1) inhibitor PD98059 was without significant effect on either insulin- or EGF-induced [³H]thymidine incorporation. Insulin treatment did not alter levels of messenger RNAs (mRNAs) for c-fos, c-jun, and c-myc. EGF induced an increase in c-myc, but not c-fos or c-jun, mRNA levels in subconfluent hepatocyte cultures. This increase in c-myc mRNA was abolished by PD98059. In confluent cells that could not be induced to synthesize DNA, EGF treatment also promoted an increase in c-myc mRNA to levels seen in subconfluent cultures. This increase was also abrogated by PD98059. These data indicate that in primary rat hepatocyte cultures, 1) the phosphoinositol 3-kinase pathway, perhaps through p70^s6k activation, regulates DNA synthesis in response to insulin and EGF; 2) the MAPK pathway is not involved in insulin- and EGF-induced DNA synthesis; and 3) p44/42 MAPKs are involved the induction of c-myc mRNA levels, although this induction is not required for DNA synthesis. These studies define two distinct signal transduction pathways that independently mediate growth-related responses in a physiologically relevant, normal cell system.

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