Interaction of insulin, glucocorticoids, and protein kinase C in the regulation of insulin-like growth factor-binding protein-1 production by H4IIE rat hepatoma cells.
A sensitive RIA was used to examine regulation of IGFBP-1 in H4IIE rat hepatoma cells. IGFBP-1 was stimulated up to tenfold by dexamethasone and corticosterone, and this stimulation was abolished by RU486. The effect of dexamethasone increased with time in culture. Phorbol 12-myristate 13-acetate (PMA) stimulated IGFBP-1 up to fourfold with a maximal effect in short-term culture. Dexamethasone and PMA were additive in stimulating IGFBP-1. Under basal conditions IGFBP-1 production was linearly related to cell density: however, stimulation by dexamethasone was greatest in confluent cells, and PMA had a greater effect in sparse cultures. Insulin inhibited IGFBP-1 up to 80%, and this effect diminished with time in culture but was unaffected by cell density. Dexamethasone was stimulatory in the presence of a maximal inhibitory concentration of insulin, and insulin was inhibitory in the presence of maximal dexamethasone from 3-48 h in culture, regardless of cell density. PMA abolished the inhibitory action of insulin on IGFBP-1 secretion and mRNA expression during incubation periods of less than 4 h and not during longer incubations. PMA did not influence the stability of IGFBP-1 mRNA. We conclude that, in rat H4IIE cells, dexamethasone and PMA stimulate IGFBP-1 by independent mechanisms and speculate that when protein kinase C is activated the inhibitory action of insulin is blocked.
Lewitt
M S
MS
Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia.
Saunders
H
H
Baxter
R C
RC
D000818:Animals; D006528:Carcinoma, Hepatocellular; D002452:Cell Count; D003345:Corticosterone / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism*; D011863:Radioimmunoassay; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000166:cytology
D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D003907:Dexamethasone; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D003345:Corticosterone