RAPID CHANGES IN GENE-EXPRESSION AFTER IN-VIVO GROWTH-HORMONE TREATMENT

GH exerts long-lasting effects on somatic growth via changes in gene expression and protein biosynthesis that represent the culmination of signal transduction pathways initiated at the cell surface. Recent studies have demonstrated that ligand-induced activation of the GH receptor leads to the phosphorylation of multiple intracellular proteins, including latent cytoplasmic transcription factors, Stats 1 and 3. GH treatment also has been found to induce the expression of several genes in both in vitro and in vivo systems, and we have shown that GH rapidly activates insulin-like growth factor I (IGF-I) gene transcription in hypophysectomized rats. In this study, using the GH-deficient, hypophysectomized rat as a model, we have examined the earliest changes in gene expression that follow a single systemic injection of GH. We find that GH induces nascent nuclear IGF-I transcripts within 15 min of hormone treatment, a time course that parallels the GH-regulated appearance of nuclear c-fos messenger RNA (mRNA). By contrast, nuclear transcripts for c-jun did not increase in abundance until after 30 min after hormone injection, and the peak rise in c-jun mRNA was severalfold less than for c-fos or IGF-I. GH treatment also led to the acute inhibition of IGF binding protein-1 (IGFBP-1) and albumin gene expression. Nuclear IGFBP-1 mRNA levels declined to 60% of baseline at 30 min and to 30% at 60 min, in agreement with previous studies showing a reduction in IGFBP-1 transcription after GH. Nascent nuclear albumin transcripts also decreased in abundance after GH treatment to levels that were less than 20% of basal values at 30 and 60 min. Our results show that GH can acutely activate and inhibit gene expression in the liver. It is likely that these diverse effects of GH are mediated by multiple signal transduction pathways.