INTERMITTENT PLASMA GROWTH-HORMONE TRIGGERS TYROSINE PHOSPHORYLATION AND NUCLEAR TRANSLOCATION OF A LIVER-EXPRESSED, STAT 5-RELATED DNA-BINDING PROTEIN - PROPOSED ROLE AS AN INTRACELLULAR REGULATOR OF MALE-SPECIFIC LIVER GENE-TRANSCRIPTION

Growth hormone (GH) exerts sexually dimorphic effects on liver gene transcription that are regulated by the temporal pattern of pituitary GH release, which is intermittent in male rats and nearly continuous in females. To investigate the influence of these GH secretory patterns on intracellular hepatocyte signaling, we compared the pattern of Liver nuclear protein tyrosine phosphorylation in male and female rats. An M(r) similar to 93,000 polypeptide, p93, was found to be tyrosine phosphorylated to a high level in male but not female rats. GH, but not prolactin, rapidly stimulated p93 tyrosine phosphorylation in hypophysectomized rats. Intermittent plasma GH pulses triggered repeated p93 phosphorylation, while continuous GH exposure led to desensitization and a dramatic decline in Liver nuclear p93. p93 was cross-reactive with two monoclonal antibodies raised to mammary Stat 5, whose tyrosine phosphorylation is stimulated by prolactin. Intermittent GH pulsation translocated Liver Stat 5/p93 protein from the cytosol to the nucleus and also activated its DNA binding activity, as demonstrated using a mammary Stat 5-binding DNA element derived from the beta-casein gene. p93 is thus a liver-expressed, Stat 5-related DNA binding protein that undergoes tyrosine phosphorylation and nuclear translocation in response to intermittent plasma GH stimulation and is proposed to be an intracellular mediator of the stimulatory effects of GH pulses on male-specific liver gene expression.