Regulation of Growth Hormone (GH) Bioactivity by a Recombinant Human GH-Binding Protein*

Lim, Lanny; Spencer, Steven A.; McKay, Patrick; Waters, Michael J.

doi:10.1210/endo-127-3-1287

Cited by 150 publications

(60 citation statements)

References 26 publications

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“…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 GHBP with an ED 50 of 10 nM. The inhibition of GH-stimulated STAT5-mediated transcription is in accord with previous demonstrations that exogenous GHBP inhibits GH-stimulated function (16).…”

Section: Effect Of Exogenous Ghbp On Gh-stimulated Stat5-mediated Trasupporting

confidence: 88%

“…DISCUSSION We have described here a new functional and ligand-independent role for the soluble extracellular domain of the growth hormone receptor otherwise known as the GHBP. Exogenously applied GHBP behaves as expected (16) and inhibits the cellular response to GH in vitro. In contrast, endogenously produced GHBP functions as an enhancer of cytokine receptor-stimulated STAT5-mediated transcription.…”

Section: Nls-ghbp Enhances Stat5-mediated Transcription Stimulated Bysupporting

confidence: 56%

“…An analogous GHBP exists in other species (13), such as humans, but is derived by proteolytic cleavage of the full-length membranebound receptor (14), presumably by the action of specific metalloproteases (15). The GHBP has been demonstrated to compete with the receptor for ligand binding in the extracellular space and has been shown to inhibit the cellular response to GH in vitro (16,17). In vivo, the GHBP has been demonstrated to increase the biological activity of GH by prolongation of the half-life of plasma GH (18).…”

Section: Growth Hormone (Gh)mentioning

confidence: 99%

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The Growth Hormone-binding Protein Is a Location-dependent Cytokine Receptor Transcriptional Enhancer

Graichen

Sandstedt²,

Goh

et al. 2003

Journal of Biological Chemistry

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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. 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).The GH receptor was the first cloned member of the now extensive cytokine receptor superfamily, which includes the receptors for prolactin (PRL), erythropoietin (EPO), granulocyte colony-stimulating factor, granulocyte-macrophage colony stimulating factor, ciliary neutrophic factor, thrombopoietin, leptin, cardiotrophin I, and the ␤-chain of interleukin (IL)-2 through IL-7, IL-9, and IL-11 to IL-13 (3). Most receptors of the cytokine receptor superfamily exist in a soluble and transmembrane form (4 -7). The function of the transmembrane forms is well documented and includes signal transduction predominantly but not exclusively through the JAK-STAT pathway, resulting in gene transcription (8, 9). The role of the soluble cytokine receptors, with the notable exception of the soluble forms of the IL-6 and ciliary neurotropitir factor (CNTF) receptors (10, 11), appears confined to ligand sequestration in the extracellular space with a consequent impairment of the cellular response to exogenous ligand (4).A soluble rat growth hormone-binding protein (GHBP) exists that is derived from the GH receptor gene by an alternative mRNA splicing mechanism such that the transmembrane and intracellular domains of the GH r...

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Section: Effect Of Exogenous Ghbp On Gh-stimulated Stat5-mediated Trasupporting

confidence: 88%

Section: Nls-ghbp Enhances Stat5-mediated Transcription Stimulated Bysupporting

confidence: 56%

Section: Growth Hormone (Gh)mentioning

confidence: 99%

See 1 more Smart Citation

The Growth Hormone-binding Protein Is a Location-dependent Cytokine Receptor Transcriptional Enhancer

Graichen

Sandstedt²,

Goh

et al. 2003

Journal of Biological Chemistry

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“…The differences in the developmental patterns of the GHBP and GHR mRNA in kidney and lung may also indicate differential regulation of the two transcripts in a more physiologic model. Although their functional interplay is not understood, the GHBP may compete with the GHR for GH binding (5,6). The GHBP, therefore, might serve as a storage protein that smooths out the pulsatile exposure of cells to GH and thereby regulates the availability of GH to the membrane-bound receptor (6).…”

Section: Liver Kidney Ileum Lungmentioning

confidence: 99%

“…The soluble GHR, the GHBP, appears to be an alternatively spliced product of the GHR gene in rats (4) that is composed of the extracellular domain of the GHR but that has a unique 17-amino acid hydrophilic tail instead of the transmembrane and intracellular domains of the receptor. The function of the GHBP has not been defined; however, in vitro studies indicate that it may compete with the GHR for G H binding (5,6). As a potential competitor for ligand binding, the GHBP may have a role distinct from that of the GHR in modulating tissue responses to circulating GH.…”

mentioning

confidence: 99%

Tissue-Specific Developmental Regulation of the Messenger Ribonucleic Acids Encoding the Growth Hormone Receptor and the Growth Hormone Binding Protein in Rat Fetal and Postnatal Tissues

et al. 1992

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ABSTRACT. Tissue responsiveness to growth hormone is likely to be regulated by local concentrations and availability of the membrane-bound growth hormone receptor (GHR) and perhaps by the actions of the soluble growth hormone binding protein (GHBP). To determine whether the developmental regulation of the GHR and GHBP might vary among tissues, we have measured the relative abundance of the 4.3-kb GHR and 1.3-kb GHBP mRNA in rat fetal and postnatal liver, kidney, lung, and ileum by Northern hybridization of polyadenylated RNA with a 32P-labeled antisense riboprobe prepared from a rat GHR cDNA. The GHR and GHBP mRNA were both present in the four tissues studied at fetal age 19 d (E19). In postnatal liver, both transcripts increased in abundance 3-to 4-fold after 14 d to mature levels at 42 d ( p = 0.0001). Similar changes were seen in postnatal kidney for GHR mRNA abundance; however, GHBP mRNA abundance increased only 2-to 3-fold to mature levels by 28 d (kidney GHR versus GHBP mRNA profile, p = 0.0001). In lung, a 2-fold linear increase in GHR mRNA abundance was observed (p = 0.0019), but the GHBP mRNA did not change (GHR versus GHBP mRNA profile, p = 0.0006). Both transcripts decreased in abundance by 2-to 3-fold from E l 9 to 42 d in ileum (p < 0.05). The abundance of both transcripts was three to 10 times greater in 60-d liver than in the other three tissues at 60 d. The variation in abundance and in the developmental profiles of the GHR and GHBP mRNA observed in these fetal and postnatal tissues suggests that the GHR and GHBP could mediate differences within and between tissues in the responsiveness to growth hormone. The differential regulation of the two transcripts evident in kidney and lung supports the emerging evidence that the GHBP may have a function distinct from that of the GHR. (Pediatr Res 31: 335-339, 1992) Abbreviations GH, growth hormone GHR, growth hormone receptor GHBP, growth hormone binding protein poly A+, polyadenylated RNA

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Postnatal Variations of Growth Hormone Bioactivity and of Growth Hormone-Dependent Factors

Bozzola

Tettoni

Locatelli³

et al. 1996

Arch Pediatr Adolesc Med

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Regulation of Growth Hormone (GH) Bioactivity by a Recombinant Human GH-Binding Protein*

Cited by 150 publications

References 26 publications

The Growth Hormone-binding Protein Is a Location-dependent Cytokine Receptor Transcriptional Enhancer

The Growth Hormone-binding Protein Is a Location-dependent Cytokine Receptor Transcriptional Enhancer

Tissue-Specific Developmental Regulation of the Messenger Ribonucleic Acids Encoding the Growth Hormone Receptor and the Growth Hormone Binding Protein in Rat Fetal and Postnatal Tissues

Postnatal Variations of Growth Hormone Bioactivity and of Growth Hormone-Dependent Factors

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