Zinc Mediation of the Binding of Human Growth Hormone to the Human Prolactin Receptor

Cunningham, Brian C.; Bass, Steven; Fuh, Germaine; Wells, James A.

doi:10.1126/science.2270485

Cited by 270 publications

(153 citation statements)

References 39 publications

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“…11). Human GH is also a ligand for the PRL receptor (44), and therefore an activation of the PRL receptor and a STAT5-mediated transcriptional response to hGH via the PRL receptor can be expected (27). STAT5-mediated transcription, stimulated specifically through the PRL receptor either with hGH or with ovine PRL, was also enhanced in the presence of NLS-GHBP to a similar extent as the enhancement of STAT5-mediated transcription by NLS-GHBP through the GH receptor.…”

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

confidence: 95%

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: Nls-ghbp Enhances Stat5-mediated Transcription Stimulated Bymentioning

confidence: 95%

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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“…Considera-se que a relação entre zinco e sinais de membrana na regulação hormonal, melhora a interação entre os hormônios e seus receptores, como observado no hormônio do crescimento e prolactina (19). Neste contexto, outra ação atribuída ao zinco, refere-se ao estímulo pós-receptor, que aumenta a translocação dos transportadores de glicose dos seus sítios intracelulares para a membrana plasmática (20).…”

Section: Bases Bioquímicas Da Deficiência De Zincounclassified

Alterações metabólicas e funcionais do zinco em diabetes mellitus

Pedrosa

Cozzolino

1998

Arq Bras Endocrinol Metab

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RESUMOO objetivo desta revisão foi relatar as alterações metabólicas e fisiológi-cas do zinco na presença do diabetes mellitus. O zinco é componente de várias enzimas e participa de vias metabólicas que envolvem a sín-tese de proteínas, metabolismo de carboidratos, de lipídeos e de ácidos nucléicos. Este mineral tem sido relacionado com a interação entre hormônios e seus receptores, e com melhoras no estímulo pós receptor. Estudos in vitro apontam que a insulina pode se complexar com o zinco melhorando a solubilidade e estocagem deste hormônio nas células beta do pâncreas. Em diabetes mellitus experimental, tem sido detectado alterações na concentração e na distribuição de zinco nos tecidos, assim como hiperzincúria logo após a indução da doença. Em pacientes com diabetes do tipo 1 ou tipo 2, as avaliações bioquímicas têm demonstrado concentrações de zinco no plasma inversamente proporcionais ao tempo de duração da doença, baixos valores em células sangüíneas, assim como hiperzincúria logo após a indução da doença. O mau controle metabólico nestes pacientes pode estar associado à depleção intracelular de zinco, predispondo a alterações no estado nutricional deste mineral. O conhecimento das funções do zinco no metabolismo de nutrientes, no crescimento, no sistema imunológico e nos tecidos oculares tem gerado especulações em relação ao envolvimento da deficiência deste micronutriente na gênese de algumas complicações da doença. ABSTRACTThe aim of this review is to discuss physiological and metabolic alterations of zinc in diabetes mellitus. Zinc is a component of diverse enzymes and also participates in metabolic pathway involving protein synthesis, carbohydrate, and metabolism of lipid and nucleic acids. This mineral has been related to the interaction between hormones and their receptors including the improvement of post receptor stimuli. In vitro studies demonstrate that insulin can bind to zinc improving the solubility and the storage of this hormone in the islets of Langerhans. In experimental diabetes alterations in zinc concentration and distribution have been detected, as well as hyperzincuria immediately after induction of the disease. In patients with type 1 and type 2 diabetes a negative correlation between plasma zinc and duration of the disease was observed. Other evaluations frequently show hyperzincuria. Poor metabolic control in these patients can be associated with intracellular zinc depletion, this fact can influence zinc status alterations. The knowledge of zinc functions are important to nutrient metabolism, growth, immune system and eye and have prompted especulations regarding a link between zinc deficiency and the genesis of chronic diabetic complications. (Arq Bras Endocrinol Metab 1998;42/6:422-430)

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“…Human growth hormone contains three ligands that coordinate Zn2+, which forms a dimer Volume 102, Supplement 3, September 1994 that is stabilized by the metal (64). Additionally, Zn2+ in the 10 to 50 1iM range stabilizes the binding of human growth hormone to the human prolactin receptor (65), which contributes one of the four ligands that coordinate the metal. Although the physiological significance of the interaction between growth hormone and the prolactin receptor is unclear, the hormone-receptor "zinc sandwich" is a model system in which Zn2+ modulates the binding of a polypeptide hormone to a nonphysiologic receptor.…”

Section: A Zn2+ Site May Mediate the Hormonelike Responsesmentioning

confidence: 99%

“…Although the physiological significance of the interaction between growth hormone and the prolactin receptor is unclear, the hormone-receptor "zinc sandwich" is a model system in which Zn2+ modulates the binding of a polypeptide hormone to a nonphysiologic receptor. The receptors for prolactin and growth hormone do not have a high affinity site for Zn2+ or other metals (64,65 (30,55). The imidazole group of histidine (pKa 6-7) is the principle functional group with a pKa near the external pH (6.4) which half-maximally induced Ca2+ release from internal stores (30,31).…”

Section: A Zn2+ Site May Mediate the Hormonelike Responsesmentioning

confidence: 99%

Transmembrane signals and protooncogene induction evoked by carcinogenic metals and prevented by zinc.

Smith

Smith²,

Pijuan³

et al. 1994

Environ Health Perspect

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Cd2+ provokes an immediate production of inositol trisphosphate and the release of Ca2+ from internal stores in human fibroblasts and some other mammalian cells. Ni2+, Co2+, Fe2+, and Mn2+ evoke the release of stored Ca2+, but are less potent than Cd2+ (apparent Ko05 = 40 nM). Zn2+ and Cu2+ competitively inhibit Ca2+ release evoked by Cd2, without affecting Ca2+ release by hormones such as bradykinin. Zn2+ has the same apparent Ki value (80-90 nM) towards the five agonist metals, which suggests that the metals interact with the same site. Many other divalent cations neither released stored Ca2+ nor affected Cd2+-evoked Ca2+ release. The agonist metals appear to activate phospholipase C via a G protein rather than a tyrosine kinase. The production of reactive oxygen species is probably not involved in Ca2+ release by the metals. Cd2+ and other stimuli that raise cytosolic-free Ca2+ induce cyclic (AMP) production, apparently by activating a calmodulin-dependent adenylyl cyclase. We suggest that an orphan receptor mediates the hormonelike responses to Cd2+ and the other agonist metals. The receptor is referred to as an orphan because its physiological stimulus is unknown. Growth of the fibroblasts in high Zn2+ desensitizes them to the five agonist metals without affecting Ca2+ release by bradykinin or histamine. A several hour incubation in culture medium with normal Zn2+ fully restores responsiveness to the five active metals. Growth in high Zn2+ appears to repress the synthesis of the putative orphan receptor because inhibitors of RNA or protein synthesis, or asparagine-linked glycosylation, prevented the restoration of metal responsiveness. Experiments with lectins and neuraminidase support the view that a cell surface sialoprotein mediates Cd2+ responsiveness. Cd2+ evokes rapid changes in 132P] incorporation by certain proteins, as would be expected for the activation of a phospholipase C-coupled receptor. Cd2+ and the other metals that trigger hormonelike messenger production, also induce protooncogenes. These observations have revealed a new target for certain metals which is extraordinary with respect to metal potency and specificity. Additionally, the work reviewed here supports the view that certain metals can promote cell growth, which results in part from the fortuitous induction of hormonelike signals. -Environ Health Perspect 102(Suppl 3): 181-189 (1994).

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Zinc Mediation of the Binding of Human Growth Hormone to the Human Prolactin Receptor

Cited by 270 publications

References 39 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

Alterações metabólicas e funcionais do zinco em diabetes mellitus

Transmembrane signals and protooncogene induction evoked by carcinogenic metals and prevented by zinc.

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