CONTRASTING ACUTE IN-VIVO NUCLEAR ACTIONS OF GROWTH-HORMONE AND PROLACTIN

Growth hormone (GH) and prolactin (PRL) exert long-term effects on cel lular metabolism, growth, and development through changes in gene expr ession and protein biosynthesis that are initiated by hormone binding to specific cell-surface receptors. Recent studies have demonstrated t hat ligand-induced activation of both GH and PRL receptors leads to th e tyrosine phosphorylation of multiple intracellular proteins by the i dentical non-receptor tyrosine kinase, JAK2. We have shown previously that in vivo administration of human recombinant GH rapidly stimulated the inducible transcription factors, Stats1, 3, and 5, and acutely al tered gene transcription in the liver. Because human GH can bind to bo th lactogenic and somatogenic receptors with high affinity, in this st udy we have addressed the question of specificity of the hormonal resp onse by examining the early nuclear events following a single injectio n of rat GH or rat PRL to hormone-deficient hypophysectomized female r ats. We find that PRL stimulated tyrosine phosphorylation of Stat5, in duced nuclear protein binding to the GH-responsive element of the seri ne protease inhibitor (Spi) 2.1 promoter, and activated Spi 2.1 gene e xpression. These acute actions of rat PRL were modest compared to the effects of rat GH. GH treatment induced tyrosine phosphorylation of se veral hepatic nuclear proteins, activated Stats1, 3, and 5,. stimulate d Spi 2.1 gene expression, and inhibited albumin gene transcription. A ll of the effects of rat GH paralleled responses to human GH that we h ave measured previously. Based on these results, it is likely that mos t of the actions of human GH in the liver are mediated by the GH recep tor rather than by the PRL receptor. The diminished response to PRL ma y be secondary to the high density of short PRL receptor isoforms in t he liver, which do not participate effectively in ligand-induced signa l transmission.