Structure and regulation of expression of the mouse GH receptor

Abstract

GH-binding protein (GHBP) in the mouse consists of a ligand-binding domain, which is identical to the extracellular portion of the GH receptor (GHR), and a hydrophilic C-terminal domain, in place of the transmembrane and intracellular domains of the GHR. The two proteins are encoded by separate mRNAs which are derived from a single gene by alternative splicing. Determination of the gestational profiles of GHR and GHBP mRNA expression in mouse liver and placenta shows that in the liver, the 1·4 kb mRNA corresponding to the mouse GHBP increases approximately 20-fold between non-pregnant and late pregnant mice, whereas the relative increase in the expression of the 4·2 kb mouse GHR was 8-fold. The rise in the steady-state levels of both mRNAs began on day 9 of gestation. Mouse GHBP mRNA levels continue to rise until day 15 of pregnancy, while GHR mRNA abundance reaches a plateau by day 13. By elucidating the temporal changes in GHR and GHBP mRNA abundance during pregnancy and lactation in multiple maternal tissues and by assessing the ontogeny of these mRNAs in fetal and early postnatal mouse liver, our studies have demonstrated that the alternative splicing of mouse GHR/GHBP mRNA precursor is regulated in a tissue-, developmental stage-and physiological state-specific manner. In vitro studies using hepatocytes in culture have begun to elucidate the hormonal factor(s) involved in the gestation control of the expression of GHR and GHBP. Treatment of hepatocytes with GH or estradiol (E2) alone did not have any effect on the cellular concentrations of GHBP and GHR. However, the combination of E2 and GH up-regulated the cellular concentrations of GHBP and GHR 2-to 3-fold. GHBP and GHR mRNA concentrations were also up-regulated 2-to 3-fold. ICI 182-780, a competitive inhibitor of E2 for the estrogen receptor (ER), at different concentrations inhibited the E2-and GH-induced stimulation of GHBP and GHR. Furthermore, ER concentrations increased 5-to 7-fold in hepatocytes treated with E2 and GH compared with those in untreated cells or cells treated with either E2 or GH alone. Our studies in the mouse suggest that GHBP is an important cell-surface receptor for GH in the liver. These studies postulate that an arginine-glycine-aspartic acid sequence found on mouse GHBP but absent in other species is responsible for the association of GHBP with the plasma membrane by binding to one or more integrins on the surface of liver cells.

Long isoform of prolactin receptor predominates in rat intrahepatic bile ducts and further increases under obstructive cholestasis

“…Female and male sex hormones act on the alternative splicing of PrlR premRNA in rat hepatocytes in a unidirectional manner: they increase the preferential inclusion of the distal exon into mature mRNA (Table 3), although with different efficacies. The effect of oestrogens on alternative splicing resulting in preferential usage of the distal exon was demonstrated for growth hormone receptor pre-mRNA in mouse hepatocytes (Talamantes & Ortiz 2002) and for PrlR pre-mRNA in rat hepatocytes (Sakaguchi et al 1994). The level of long PrlR isoforms in normal cholangiocytes is almost equal to that found in hepatocytes of male and female rats (Tables 2 and 3).…”

Bone metabolism in relation to alterations in systemic growth hormone

“…The primary transcript that generates GHR mRNA can undergo alternate splicing to produce several related mRNAs, including transcripts that encode the circulating GHBP and a truncated GHR that inhibits normal cellular responses to GH in vitro [10]. Binding of GH to GHR induces receptor dimerization and activation of the tyrosine kinase, JAK2, which in turn activates signalling molecules, including Stat (signal transducer and activator of transcription) factors, Src homologous collagen protein and insulin receptor substrates 1 and 2 [10]. Excluding insulin, the IGF family includes two ligands, IGF-I and IGF-II, which are highly homologous mitogenic peptides.…”

Effect of glycerol on GHR and IGF-1 gene expression in breast muscle and on growth of Japanese meat quails

“…The capacity of target cells to respond to GH depends mainly on the expression of GHR (Talamantes and Ortiz, 2002). Therefore, the higher IGF-1 mRNA levels observed in birds fed 12% glycerol in the present study may have reduced GH levels by negative feedback, consequently reducing the need and the levels of GHR mRNA in these birds.…”