Structure of a genomic clone encoding biologically active human relaxin

Hudson, Peter J.; Haley, John D.; John, M.; Cronk, M.; Crawford, Robert J.; Haralambidis, Jim; Tregear, Geoffrey W.; Shine, John; Niall, Hugh D.

doi:10.1038/301628a0

Cited by 230 publications

(114 citation statements)

References 34 publications

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“…This P1 clone has a genomic DNA insert of approximately 80 kb estimated by restriction mapping and Southern blotting, large enough to contain both full-length relaxin genes, each estimated to have a size of approximately 7-9 kb (Hudson et al 1983). The presence of the relaxin H1 and H2 genes in the P1 clone was confirmed through PCR amplification and Southern blotting using a full-length (558 bp) relaxin H2 cDNA as a probe (data not shown).…”

Section: Breakpoint Mapping By Fishmentioning

confidence: 85%

Analysis of the 5'-upstream regions of the human relaxin H1 and H2 genes and their chromosomal localization on chromosome 9p24.1 by radiation hybrid and breakpoint mapping

Garibay-Tupas¹,

Csiszár²,

Fox³

et al. 1999

Journal of Molecular Endocrinology

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Relaxins are known endocrine and autocrine/ paracrine hormones that play a major role in reproduction. In the human there are two relaxin genes, H1 and H2 which share 90% sequence homology within their coding region. The biological and evolutionary significance of two highly homologous and biologically active human relaxins is unknown. In order to achieve a better understanding of the regulatory mechanisms involved in the differential expression of these two genes and to gain insight into their role(s) in the preterm premature rupture of the membranes, we have investigated the properties of their 5 -upstream regions and mapped them both by radiation hybrid and breakpoint mapping into the same chromosome 9p24·1 locus. The 5 ends of these relaxin genes could be divided into a proximal highly homologous segment and a distal non-homologous region. Within the proximal region are contained several putative regulatory elements common to both genes, suggesting a similar regulatory mechanism. The clustering of the relaxin genes within the same chromosomal locus suggests that these genes may be under a common regulation. On the other hand, a distinct gene-specific regulation may also exist for the individual relaxin genes since cis elements specific to each gene were identified at their 5 ends. Moreover, the observed divergence at the distal region of their 5 -upstream sequences may provide the structural features that act as gene-specific transcription regulators. Since the two genes are highly homologous in both their coding and flanking regions, the divergence at the distal region of their 5 ends may be important in the regulation of these genes and in their involvement in the pathology of preterm birth.

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Section: Breakpoint Mapping By Fishmentioning

confidence: 85%

Analysis of the 5'-upstream regions of the human relaxin H1 and H2 genes and their chromosomal localization on chromosome 9p24.1 by radiation hybrid and breakpoint mapping

Garibay-Tupas¹,

Csiszár²,

Fox³

et al. 1999

Journal of Molecular Endocrinology

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“…Relaxin-3 (INSL 7) is a recently identified peptide member of the insulin superfamily, typified by the presence of an A and B chain linked by inter-and intrachain disulphide bonds [1]. Like insulin, the intervening C peptide chain of relaxin-3 is removed by proteolytic processing.…”

Section: Introductionmentioning

confidence: 99%

Effects of acute and chronic relaxin-3 on food intake and energy expenditure in rats

McGowan

Stanley

Smith

et al. 2006

Regulatory Peptides

119

158

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The effects of acute and repeated intraparaventricular (iPVN) administration of human relaxin-3 (H3) were examined on food intake, energy expenditure, and the hypothalamic-pituitary thyroid axis in male Wistar rats. An acute high dose iPVN injection of H3 significantly increased food intake 1 hour post-administration [0.4 ± 0.1g (vehicle) vs 1.6 ± 0.5g (180pmol H3), 2.4 ± 0.5g (540pmol H3) and 2.2 ± 0.5g (1620pmol H3), p< 0.05 for all doses vs vehicle]. Repeated iPVN H3 injection (180pmol/twice a day for 7 days) significantly increased cumulative food intake in ad libitum fed animals compared with vehicle [211.8 ± 7.1g (vehicle) vs 261.6 ± 6.7g (ad libitum fed H3), p< 0.05]. Plasma leptin was increased in the H3 ad libitum fed group. Plasma thyroid stimulating hormone was significantly decreased after acute and repeated administration of H3. These data suggest H3 may play a role in longterm control of food intake.

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“…Recently, two leucine-rich repeat-containing G-protein-coupled receptors (LGRs), 1 LGR7 and LGR8 (2,3), have been identified as the receptors for relaxin (3)(4)(5)(6)(7).…”

mentioning

confidence: 99%

Identification of Relaxin-3/INSL7 as a Ligand for GPCR142

Liu

Chen

Sutton

et al. 2003

Journal of Biological Chemistry

227

272

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We have recently identified the insulin-like peptide relaxin-3 (aka INSL7) as the endogenous ligand for an orphan G-protein-coupled receptor, GPCR135 (aka somatostatin-and angiotensin-like peptide receptor). Analysis of possible receptors related to GPCR135 revealed a single orphan receptor, GPCR142. Thus, we tested whether GPCR142 could also respond to relaxin-3 or related insulin-like molecules. Surprisingly, GPCR142 was activated by nanomolar concentrations of relaxin-3 but was completely unresponsive to all other known insulin-like peptides. We evaluated by reverse transcriptase-PCR the expression of GPCR142 mRNA in a variety of human tissues and found expression in brain, kidney, testis, thymus, placenta, prostate, salivary gland, thyroid, and colon. In an analysis of other species, we were able to find a full-length mouse homolog of GPCR142, but were unable to detect any complete GPCR142 transcripts in rat. With respect to intracellular signaling, GPCR142 is similar to GPCR135 in that it potently inhibits adenylate cyclase and stimulates 35 S-GTP␥S incorporation in response to relaxin-3. However, whereas GPCR135 signaling could be converted to calcium mobilization using a G qi5 or G␣ 16 G-proteins, GPCR142 was only capable of functioning in the presence of G␣ 16 . In the accompanying article (Liu, C., Eriste, E., Sutton, S., Chen, J., Roland, B., Kuei, C., Farmer, N., Jö rnvall, H., Sillard, R., and Lovenberg, T. W. (2003) J. Biol. Chem. 278, 50754 -50764), we present the case that relaxin-3, which has previously been shown to bind to the relaxin receptor LGR7, is most likely the endogenous ligand for GPCR135. In this report, we show an additional receptor, GPCR142, which is also selectively activated by relaxin-3. However, the anatomical localization of GPCR142 suggests that GPCR142 may have different physiological functions.Relaxin-3 (1) is a member of the insulin superfamily, where each member consists of two peptide subunits arranged by three disulfide bridges. Recently, two leucine-rich repeat-containing G-protein-coupled receptors (LGRs), 1 LGR7 and LGR8 (2, 3), have been identified as the receptors for relaxin (3-7).LGR7 and LGR8 belong to the type III hormone receptor family (follicle stimulating hormone (FSH), luteinizing hormone (LH), and thyroid stimulating hormone (TSH) etc. that stimulate adenylate cyclase). Relaxin-3 was recently demonstrated to be an additional ligand for the relaxin receptor LGR7, but not LGR8 (8). Instead, the ligand INSL3 (9), another member of the insulin/relaxin family of peptides, has been shown to be an additional ligand for LGR8 (10).As part of a directed effort to identify ligands for orphan G-protein-coupled receptors (GPCRs), we established a systematic program to create tissue extracts as a source of possible GPCR ligands. In the accompanying article (23), we report the purification and identification of the peptide ligand, relaxin-3, as an endogenous ligand for orphan receptor GPCR135, aka SALPR (somatostatin-and angiotensin-like peptide receptor).In that report...

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Structure of a genomic clone encoding biologically active human relaxin

Cited by 230 publications

References 34 publications

Analysis of the 5'-upstream regions of the human relaxin H1 and H2 genes and their chromosomal localization on chromosome 9p24.1 by radiation hybrid and breakpoint mapping

Analysis of the 5'-upstream regions of the human relaxin H1 and H2 genes and their chromosomal localization on chromosome 9p24.1 by radiation hybrid and breakpoint mapping

Effects of acute and chronic relaxin-3 on food intake and energy expenditure in rats

Identification of Relaxin-3/INSL7 as a Ligand for GPCR142

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