Abstract
In the rat, a growth hormone-binding protein (GHBP) exists that is derived from the growth hormone (GH) receptor gene by an alternative mRNA splicing mechanism such that the transmembrane and intracellular domains of the GH receptor are replaced by a hydrophilic carboxyl terminus. In isolation, the GHBP is inactive, although it does compete with the receptor for ligand binding in the extracellular space and therefore inhibits the cellular response to GH. The GHBP is also located intracellularly and is translocated to the nucleus upon ligand stimulation. We show here that endogenously produced GHBP, in contrast to exogenous GHBP, was able to enhance the STAT5-mediated transcriptional response to GH. Interestingly, when the GHBP was targeted constitutively to the nucleus by the addition of the nuclear localization sequence of the SV40 large T antigen, greater enhancement of STAT5-mediated transcription was obtained. The transcriptional enhancement did not require GH per se and was not specific to the GH receptor, since similar enhancement of STAT5-mediated transcription by nuclear localized GHBP was obtained with specific ligand stimulation of both prolactin and erythropoietin receptors. Thus, the GHBP exerts divergent effects on STAT5-mediated transcription depending on its cellular location. The use of a soluble cytokine receptor as a location-dependent transcriptional enhancer and the ligand-independent involvement of the extracellular domain of a polypeptide ligand receptor in intracellular signal transduction provide additional novel mechanisms of transcriptional control.
Highlights
Growth hormone (GH)1 is the major regulator of postnatal body growth and initiates its biological actions, including the induction of a number of RNA species in mammalian tissues, by interaction with a specific membrane-bound receptor [1, 2]
With the GH concentration fixed at 1 nM, a dose-dependent inhibition of GH-stimulated STAT5-mediated transcription was observed over the range of 1–100 nM growth hormone-binding protein (GHBP) with an ED50 of 10 nM
nuclear localization sequence (NLS)-GHBP Enhances STAT5-mediated Transcription Stimulated by Other Members of the Cytokine Receptor Superfamily—Since the GHBP could enhance STAT5-mediated transcription without bound ligand, we examined whether NLSGHBP could function as a transcriptional enhancer for other cytokine receptor superfamily members that utilize STAT5 for transcriptional activation [43]
Summary
Growth hormone (GH)1 is the major regulator of postnatal body growth and initiates its biological actions, including the induction of a number of RNA species in mammalian tissues, by interaction with a specific membrane-bound receptor [1, 2]. We demonstrate here that nuclear localized GHBP functions as a potent enhancer of STAT5-mediated transcription, for GH and for other members of the cytokine receptor superfamily. We first used the BRLGHR1–638 cells to demonstrate the effect of exogenously added recombinant rat GHBP on GH-stimulated STAT5-mediated transcription utilizing a reporter plasmid containing the STAT5 binding element of the serine protease inhibitor 2.1 gene promoter (SPI-GLE1-CAT) [31].
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