Growth hormone receptor structure, dimerization and function

Kelly, P. A.; Postel-Vinay, Marie-Catherine; Finidori, J.; Edery, Marc; Sotiropoulos, Athanassia; Goujon, Laure; Esposito, Nazario

doi:10.1111/j.1651-2227.1994.tb13301.x

Cited by 8 publications

(4 citation statements)

References 33 publications

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“…Are the 5' and/or 3 skipped existed either within or directly adjacent to the 5' and 3' splice sites of the introns flanking exon 3 in the hGHR gene in those individuals expressing 100% hGHRd3. Genomic DNA was isolated from 10 individuals expressing 100% hGHRwt, 100% hGHRd3, or both isoforms.…”

Section: Resultsmentioning

confidence: 99%

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Alternative splicing of exon 3 of the human growth hormone receptor is the result of an unusual genetic polymorphism.

Stallings-Mann

Ludwiczak

Klinger

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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Two isoforms of the human growth hormone receptor (hGHR), which differ in the presence (hGHRwt) or absence (hGHRd3) of exon 3, are expressed in the placenta. Specifically, three expression patterns are observed: only hGHRwt, only hGHRd3, or an approximately 1:1 combination of both isoforms. We investigated several potential regulatory mechanisms which might account for the expression of the hGHR isoforms. The frequency of hGHRd3 expression did not change when placentas from differing stages of gestation were examined, suggesting splicing was not developmentally regulated. However, when hGHR isoform expression patterns were examined in each component of a given placenta, it was evident that alternative splicing of exon 3 is individualspecific. Surprisingly, the individual-specific regulation of hGHR isoforms appears to be the result of a polymorphism in the hGHR gene. We analyzed hGHRwt and hGHRd3 expression in Hutterite pedigrees, and our results are consistent with a simple Mendelian inheritance of two differing alleles in which exon 3 is spliced in an "all-or-none" fashion. We conclude the alternative splicing of exon 3 in hGHR transcripts is the result of an unusual polymorphism which significantly alters splicing of the hGHR transcript and that the relatively high frequency ("10O%) of homozygous hGHRd3 expression suggests the possibility it may play a role in polygenic determined events.In humans, chorionic somatomammotropin (hCS) and growth hormone (hGH) are encoded by a family of genes clustered on chromosome 17 (1). At least two forms of each hormone are encoded by separate genes for both hCS (hCS-A and hCS-B) and hGH (hGH-N and hGH-V). hGH-N, which is expressed only in the anterior lobe of the pituitary, is best known for its effects on the growth of skeletal and soft tissues and for its metabolic actions. The remaining proteins are expressed exclusively in the placenta. Their precise function remains obscure, and the picture is further complicated by the presence of alternatively spliced mRNAs that can give rise to additional isoforms.The synthesis and secretion of hCS, hGH-V, and their multiple isoforms in the placenta raises an important question as to whether a single receptor mediates the activity of these proteins or if different receptors exist. A receptor for hGH (hGHR) has been cloned (2) and shown to belong to the cytokine receptor family (3). A second, alternatively

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Section: Resultsmentioning

confidence: 99%

“…A receptor for hGH (hGHR) has been cloned (2) and shown to belong to the cytokine receptor family (3). A second, alternatively spliced, form of hGHR lacking exon 3 (hGHRd3) was recently identified from a placental cDNA library (4).…”

mentioning

confidence: 99%

Alternative splicing of exon 3 of the human growth hormone receptor is the result of an unusual genetic polymorphism.

Stallings-Mann

Ludwiczak

Klinger

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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“…These molecules include receptors for growth hormones (1,2), steroid hormones (3), other cellular signals (4,5), and numerous transcription factors (6,7). The transcriptional activators of the yeast Gal4 family also require dimerization for DNA binding and transcriptional activation (8,9).…”

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confidence: 99%

The Yeast Heme-responsive Transcriptional Activator Hap1 Is a Preexisting Dimer in the Absence of Heme

Hon

Hach

Tamalis

et al. 1999

Journal of Biological Chemistry

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In the absence of heme, Hap1 is associated with molecular chaperones such as Hsp90 and Ydj1 and forms a higher order complex termed HMC. Heme disrupts this complex and permits Hap1 to bind to DNA with high affinity, thereby activating transcription. Heme regulation of Hap1 activity is analogous to the regulation of steroid receptors by steroids, which involves molecular chaperones. Steroid receptors often exist as monomers when associated with molecular chaperones in the absence of ligand but as dimers when activated by steroids. Furthermore, previous studies indicate that dimerization might be important for heme activation of Hap1. We therefore determined whether Hap1 is a monomer or oligomer in the absence of heme. By coeluting two Hap1 size variants and by comparing DNA binding properties of the HMC and Hap1 dimer, we show that Hap1 is a preexisting dimer in the HMC. Further, increasing overexpression of Hap1 caused progressive increases in Hap1 DNA binding and transcriptional activities. Our data suggest that in the absence of heme, Hap1 exists as a dimer, and the two subunits act cooperatively in DNA binding. Hap1 repression is caused, at least in part, by inhibition of the DNA binding activity of the preexisting dimer.Dimerization is a common mechanism by which the activity of numerous important biological macromolecules can be regulated. These molecules include receptors for growth hormones (1, 2), steroid hormones (3), other cellular signals (4, 5), and numerous transcription factors (6, 7). The transcriptional activators of the yeast Gal4 family also require dimerization for DNA binding and transcriptional activation (8,9). This family includes at least 52 transcription factors that control a wide array of diverse processes ranging from carbon source utilization to oxygen utilization and drug resistance (8, 9). These members all contain a C6 zinc cluster that recognizes a CGG triplet (9 -15). Although the DNA binding properties of the C6 zinc cluster proteins are well characterized, the molecular mechanisms by which these members act to control transcription in response to various signals are largely unclear. Interestingly, recent data suggest that, like steroid hormone receptors, certain members of the yeast Gal4 family such as Hap1 and Pdr1 (16,17) are regulated by Hsp90 and Hsp70 molecular chaperones. In particular, Hap1 is a heme-responsive transcriptional activator, which promotes transcription of genes required for respiration and for controlling oxidative damage in response to oxygen/heme (18 -20). In the absence of heme, Hap1 is bound to cellular proteins including Hsp82 (the yeast homologue of Hsp90) and Ydj1, forming a higher order complex termed HMC 1 (17,21,22). Hap1 DNA binding and transcriptional activities are repressed in this complex. Heme disrupts the HMC and permits Hap1 to bind to DNA as a dimer with high affinity, thereby activating transcription. The formation and disruption of the HMC are the key events in Hap1 repression in the absence of heme and subsequent activation by heme. ...

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“…These infants required oxygen for 28 days and there was a similar trend for ROP. It is accepted that free radical generation and oxidative injury contribute to the diseases of prematurity (Kelly, 1993). If there was generalized oxidative stress in preterm infants, then concentrations of oxidant markers in plasma, such as MDA, would be expected to be higher than in healthy populations.…”

Section: Application To the Analysis Of Mda In Plasmamentioning

confidence: 99%

Determination of malondialdehyde by capillary electrophoresis, application to human plasma and relation of its levels with prematurity

Korizis

Exarchou

Michalopoulos

et al. 2001

Biomedical Chromatography

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Malondialdehyde (MDA) is considered as the most important marker for monitoring lipid peroxidation, which is strongly associated with the development of serious diseases in adults and premature neonates. In this paper we report a method for determination of free MDA in human plasma using capillary zone electrophoresis. MDA was separated and determined as conjugate with tetrabutylammonium hydrogen sulphate (TBAS). Analysis was performed using 20 mM borare, pH = 9.3, as operating buffer and detection of the MDA-TBAS adduct at 267 nm. The method has a linear range up to 80 microM with a detection limit of 0.2 microM. The method was applied to the analysis of MDA in plasma of healthy adults, normal-gestation infants and of preterm neonates. Plasma proteins were successfully removed following centrifugation through a centricon-3 membrane. Results showed that the method can be easily and accurate applied for the determination of MDA in human plasma and that the level of MDA in pretern neonates is significantly higher (p

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Growth hormone receptor structure, dimerization and function

Cited by 8 publications

References 33 publications

Alternative splicing of exon 3 of the human growth hormone receptor is the result of an unusual genetic polymorphism.

Alternative splicing of exon 3 of the human growth hormone receptor is the result of an unusual genetic polymorphism.

The Yeast Heme-responsive Transcriptional Activator Hap1 Is a Preexisting Dimer in the Absence of Heme

Determination of malondialdehyde by capillary electrophoresis, application to human plasma and relation of its levels with prematurity

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