ACUTE NUCLEAR ACTIONS OF GROWTH-HORMONE (GH) - CYCLOHEXIMIDE INHIBITSINDUCIBLE ACTIVATOR PROTEIN-1 ACTIVITY, BUT DOES NOT BLOCK GH-REGULATED SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION ACTIVATION OR GENE-EXPRESSION

The mechanisms by which GH regulates gene expression to stimulate soma tic growth and alter intermediary metabolism are unknown. We have show n previously that in vivo GH administration rapidly modifies the tyros ine phosphorylation of multiple hepatic nuclear proteins, including th e inducible transcription factors, Stat1, Stat3, and (in this report) Stat5, and have found that hormone treatment also rapidly alters gene transcription in the liver. In this study, we have used the protein sy nthesis inhibitor, cycloheximide (CHX), to investigate which of the ac ute actions of GH are primary hormonal responses and which require con current protein synthesis. We found that many of the early changes in nuclear protein tyrosine phosphorylation and in nuclear protein-DNA bi nding after GH are not blunted by CHX. The activation of insulin-like growth factor I and Spi 2.1 gene expression and the inhibition of albu min transcription also are not blocked by CHX, suggesting that these e ffects are primary consequences of GH-activated signal transduction pa thways. By contrast, CHX completely inhibits the induction of activato r protein-1 DNA-binding activity by GH, indicating that this action is secondary to the stimulation of Fos and/or Jun protein biosynthesis. Our results support the idea that multiple primary and secondary signa ling pathways contribute to the pleiotropic effects of GH on gene expr ession and provide a framework for delineating the mechanisms controll ing the acute actions of GH.