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Gene Review

RLN2  -  relaxin 2

Homo sapiens

Synonyms: H2, H2-RLX, Prorelaxin H2, RLXH2, bA12D24.1.1, ...
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Disease relevance of RLN2

  • The mRNA levels of relaxin H1 and H2 in the prostate adenocarcinoma LNCaP.FGC cell line were determined by quantitative competitive RT-PCR [1].
  • We characterized upregulated H2 relaxin gene expression during neuroendocrine differentiation of the human prostate cancer model, LNCaP [2].
  • Relaxin knockout mice exhibit age-related pulmonary fibrosis, and delivery of recombinant human H2 relaxin ameliorates fibrotic-like conditions in the mouse lung [3].
  • Whereas the fibrinogen plasma level is positively associated with coronary artery disease and myocardial infarction, the H2 allele-although exhibiting an association with elevated fibrinogen levels-was not positively associated with CAD and MI [4].
  • CONCLUSIONS: Obviously, the H2 allele of the fibrinogen H1/H2 genotype does not only influence basal fibrinogen concentrations, but particularly also the extent of fibrinogen level increase during acute phase reaction [4].

Psychiatry related information on RLN2


High impact information on RLN2

  • Cloning and DNA sequence of double-stranded copies of haemagglutinin genes from H2 and H3 strains elucidates antigenic shift and drift in human influenza virus [8].
  • Chemical synthesis of biologically active relaxin based on the sequence obtained from ovarian cDNA clones confirmed that the expressed gene (H2) encodes an authentic human relaxin [9].
  • The gene organisation of HLA-A3 closely resembles that of class I H-2 genes in mouse: it shows a signal exon, three exons encoding the three extracellular domains, one exon encoding the transmembrane region and three exons encoding the cytoplasmic domain [10].
  • INTERVENTION: Patients with confirmed acid-related symptoms were treated with high-dose histamine-2 (H2) blockers or omeprazole for 8 weeks in an open-label study [11].
  • DATA EXTRACTION: All data on the incidence of and potential predisposing factors for central nervous system reactions to H2 blockers were analyzed [5].

Chemical compound and disease context of RLN2

  • Demonstration of upregulated H2 relaxin mRNA expression during neuroendocrine differentiation of LNCaP prostate cancer cells and production of biologically active mammalian recombinant 6 histidine-tagged H2 relaxin [2].
  • Most treatment failures occurred during the first 12 h (60% overall), and haloperidol led to a dose-dependent decrease in PONV (first 12 h: 76% P, 56% H1, and 50% H2; P = 0.012) [12].
  • OBJECTIVES: To determine whether a continuous i.v. infusion of cimetidine, a histamine-2 (H2) receptor antagonist, is needed to prevent upper gastrointestinal (GI) hemorrhage when compared with placebo and if that usage is associated with an increased risk of nosocomial pneumonia [13].
  • Variables significantly associated with the development of nosocomial infections included age, weight, Pediatric Risk of Mortality (PRISM) score, device utilization ratio, antimicrobial therapy, histamine-2 (H2) receptor blocker use, immune status, parenteral nutrition, and length of stay [14].
  • Histamine 2 (H2) receptor antagonists, proton pump inhibitors, prostaglandin analogues, colloidal bismuth and sucralfate have all proved safe and effective in the initial treatment of peptic ulcer [15].

Biological context of RLN2

  • Suppression of LGR7 expression by LGR7-siRNA abolished the RLN2-mediated accelerated tumor cell motility [16].
  • We now have evidence that the human genome possesses an additional relaxin-related gene (designated human relaxin gene H2) which appears to be selectively expressed in the ovary during pregnancy [9].
  • However, we demonstrated for the first time relaxin H1 gene expression in the decidua, placental trophoblast, and prostate, and we have also shown that there are marked tissue differences in the relative amounts of expression of the H1 and H2 relaxin mRNA forms [17].
  • In view of the similarities in amino acid sequence between H1 and H2 relaxins, these antibodies to H2 relaxin are likely to detect either or both relaxins present in tissue sections [18].
  • By contrast, the most widely studied family peptides, human relaxins H1 and H2, appear to be derived from recent gene duplication in mammals [19].

Anatomical context of RLN2

  • We found the intracellular distribution of procath-L specifically altered in RLN2 transfectants, providing first evidence for selective actions of relaxin on the powerful elastinolytic cath-L production, storage, and secretion in thyroid carcinoma cells [16].
  • H2 relaxin mRNA was detected in the ovary, term placenta, decidua, and prostate gland [20].
  • Binding of human gene 2 (H2) [(33)P]-RLX, expression of RLX peptides and the LGR7 receptor was examined in the human uterus at different stages of the menstrual cycle [21].
  • The results demonstrate that the structure of the predominant relaxin in human semen plasma is derived from the product of the H2 gene, consisting of a N-terminal pyroglutamic acid A-24 A chain and a mixture of B-26 and B-27 B chains [22].
  • On the other hand, protein analysis for relaxin H1 and H2 in the decidual cells showed them to be significantly up-regulated (P <.0001, for both proteins) in patients with preterm premature rupture of the membranes compared with control subjects [23].

Associations of RLN2 with chemical compounds

  • The full spectrum of biological activities of these two polypeptides has not been examined, but transcription appears to be limited to the H2 relaxin gene in the human corpus luteum [17].
  • The stability of relaxin H1 and H2 mRNAs were compared in LNCaP cells treated with the transcription inhibitor actinomycin D (10 mM) for 0, 1, 2, 4, 8, 10, 14, or 24 h [1].
  • Deletion constructs containing portions of the 5'-flanking regions of H1 and H2 linked to the bacterial chloramphenicol acetyl transferase reporter gene were prepared [24].
  • Regulation of the human relaxin genes H1 and H2 by steroid hormones [25].
  • The effects of H2 relaxin on the biomechanical properties were, however, not followed by changes in the hydroxyproline concentration or the histology [26].

Physical interactions of RLN2

  • In contrast, unlabelled guinea-pig relaxin inhibited this binding by only 10% even at a 1000-fold greater concentration than H2, and human recombinant insulin failed to inhibit even at a million-fold concentration of unlabelled relaxin H2 [27].

Regulatory relationships of RLN2

  • Lastly, we used a reporter gene assay to demonstrate that H2 relaxin can induce the expression of prostate-specific antigen via an androgen receptor-mediated pathway [28].

Other interactions of RLN2

  • Overall, relaxin-3 adopts an insulin-like fold, but the structure differs crucially from the crystal structure of human relaxin-2 near the B-chain terminus [29].
  • Although RLN2 did not act as a mitogen, it acted as an autocrine/paracrine factor and significantly increased anchorage-independent growth and thyroid carcinoma cell motility and invasiveness through elastin matrices [16].
  • Operationally the amino acid sequence homologies between the processed H1 and H2 relaxins and hLey I-L may qualify the specificity claimed for immunostaining the human relaxins in the corpus luteum and trophoblast [30].
  • RESULTS: Biomechanical testing showed that H2 relaxin induced a biphasic weakening of human fetal membranes, an effect that was abolished after co-incubation with a collagenase inhibitor [26].
  • Moreover, PC3-Luc-H2/eGFP tumors exhibited increased VEGF transcript by reverse-transcription PCR, compared to basal levels in control animals [31].

Analytical, diagnostic and therapeutic context of RLN2

  • 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 [32].
  • A radioimmunoassay for a representative portion of the c-peptide of human relaxins (H1 and H2) was developed and validated [33].
  • MATERIALS AND METHODS: Human fetal membrane explants were incubated with H1 or H2 relaxin for 48 hours and stretched until rupture in a materials testing machine [26].
  • Chromatin immunoprecipitation analysis was used to demonstrate that p53(R273H) binds directly to the relaxin promoter, further confirming a role for H2 relaxin signaling in p53(R273H)-mediated AI CaP [28].
  • An hH2 ELISA was used to measure the secreted levels of recombinant hH2 in transfected canine (CF33.Mt) and human (MDA-MB-435) mammary cancer cell lines over a 6-d period; secreted peptide peaked on d 2 and 4 for the canine and human cell types, respectively [34].


  1. Isolation and analysis of the 3'-untranslated regions of the human relaxin H1 and H2 genes. Garibay-Tupas, J.L., Bao, S., Kim, M.T., Tashima, L.S., Bryant-Greenwood, G.D. J. Mol. Endocrinol. (2000) [Pubmed]
  2. Demonstration of upregulated H2 relaxin mRNA expression during neuroendocrine differentiation of LNCaP prostate cancer cells and production of biologically active mammalian recombinant 6 histidine-tagged H2 relaxin. Figueiredo, K.A., Palmer, J.B., Mui, A.L., Nelson, C.C., Cox, M.E. Ann. N. Y. Acad. Sci. (2005) [Pubmed]
  3. Functional expression of mouse relaxin and mouse relaxin-3 in the lung from an Ebola virus glycoprotein-pseudotyped lentivirus via tracheal delivery. Silvertown, J.D., Walia, J.S., Summerlee, A.J., Medin, J.A. Endocrinology (2006) [Pubmed]
  4. Positive association of the beta fibrinogen H1/H2 gene variation to basal fibrinogen levels and to the increase in fibrinogen concentration during acute phase reaction but not to coronary artery disease and myocardial infarction. Gardemann, A., Schwartz, O., Haberbosch, W., Katz, N., Weiss, T., Tillmanns, H., Hehrlein, F.W., Waas, W., Eberbach, A. Thromb. Haemost. (1997) [Pubmed]
  5. Central nervous system reactions to histamine-2 receptor blockers. Cantú, T.G., Korek, J.S. Ann. Intern. Med. (1991) [Pubmed]
  6. Famotidine adjunctive pharmacotherapy for schizophrenia: preliminary data. Deutsch, S.I., Rosse, R.B., Kendrick, K.A., Fay-McCarthy, M., Collins, J.P., Wyatt, R.J. Clinical neuropharmacology. (1993) [Pubmed]
  7. HLA and H2 class II transgenic mouse models to study susceptibility and protection in autoimmune thyroid disease. Kong, Y.C., Flynn, J.C., Wan, Q., David, C.S. Autoimmunity (2003) [Pubmed]
  8. Cloning and DNA sequence of double-stranded copies of haemagglutinin genes from H2 and H3 strains elucidates antigenic shift and drift in human influenza virus. Gething, M.J., Bye, J., Skehel, J., Waterfield, M. Nature (1980) [Pubmed]
  9. Relaxin gene expression in human ovaries and the predicted structure of a human preprorelaxin by analysis of cDNA clones. Hudson, P., John, M., Crawford, R., Haralambidis, J., Scanlon, D., Gorman, J., Tregear, G., Shine, J., Niall, H. EMBO J. (1984) [Pubmed]
  10. Complete nucleotide sequence of a functional class I HLA gene, HLA-A3: implications for the evolution of HLA genes. Strachan, T., Sodoyer, R., Damotte, M., Jordan, B.R. EMBO J. (1984) [Pubmed]
  11. The contribution of gastroesophageal reflux to chest pain in patients with coronary artery disease. Singh, S., Richter, J.E., Hewson, E.G., Sinclair, J.W., Hackshaw, B.T. Ann. Intern. Med. (1992) [Pubmed]
  12. Single-dose haloperidol for the prophylaxis of postoperative nausea and vomiting after intrathecal morphine. Parlow, J.L., Costache, I., Avery, N., Turner, K. Anesth. Analg. (2004) [Pubmed]
  13. Continuous intravenous cimetidine decreases stress-related upper gastrointestinal hemorrhage without promoting pneumonia. Martin, L.F., Booth, F.V., Karlstadt, R.G., Silverstein, J.H., Jacobs, D.M., Hampsey, J., Bowman, S.C., D'Ambrosio, C.A., Rockhold, F.W. Crit. Care Med. (1993) [Pubmed]
  14. Risk factors for nosocomial infection in critically ill children: a prospective cohort study. Singh-Naz, N., Sprague, B.M., Patel, K.M., Pollack, M.M. Crit. Care Med. (1996) [Pubmed]
  15. Influence of initial therapy on outcome of peptic ulcer. Korman, M.G. Scand. J. Gastroenterol. Suppl. (1995) [Pubmed]
  16. Relaxin enhances the oncogenic potential of human thyroid carcinoma cells. Hombach-Klonisch, S., Bialek, J., Trojanowicz, B., Weber, E., Holzhausen, H.J., Silvertown, J.D., Summerlee, A.J., Dralle, H., Hoang-Vu, C., Klonisch, T. Am. J. Pathol. (2006) [Pubmed]
  17. Expression of the human relaxin H1 gene in the decidua, trophoblast, and prostate. Hansell, D.J., Bryant-Greenwood, G.D., Greenwood, F.C. J. Clin. Endocrinol. Metab. (1991) [Pubmed]
  18. Human relaxins in normal, benign and neoplastic breast tissue. Tashima, L.S., Mazoujian, G., Bryant-Greenwood, G.D. J. Mol. Endocrinol. (1994) [Pubmed]
  19. Evolution of the signaling system in relaxin-family peptides. Hsu, S.Y., Semyonov, J., Park, J.I., Chang, C.L. Ann. N. Y. Acad. Sci. (2005) [Pubmed]
  20. Expression of human relaxin genes: characterization of a novel alternatively-spliced human relaxin mRNA species. Gunnersen, J.M., Fu, P., Roche, P.J., Tregear, G.W. Mol. Cell. Endocrinol. (1996) [Pubmed]
  21. Increased expression of the relaxin receptor (LGR7) in human endometrium during the secretory phase of the menstrual cycle. Bond, C.P., Parry, L.J., Samuel, C.S., Gehring, H.M., Lederman, F.L., Rogers, P.A., Summers, R.J. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  22. Human seminal relaxin is a product of the same gene as human luteal relaxin. Winslow, J.W., Shih, A., Bourell, J.H., Weiss, G., Reed, B., Stults, J.T., Goldsmith, L.T. Endocrinology (1992) [Pubmed]
  23. Decidual relaxins: gene and protein up-regulation in preterm premature rupture of the membranes by complementary DNA arrays and quantitative immunocytochemistry. Tashima, L.S., Yamamoto, S.Y., Yasuda, M., Millar, L.K., Bryant-Greenwood, G.D. Am. J. Obstet. Gynecol. (2002) [Pubmed]
  24. Characterization of human relaxin gene regulation in the relaxin-expressing human prostate adenocarcinoma cell line LNCaP.FGC. Gunnersen, J.M., Roche, P.J., Tregear, G.W., Crawford, R.J. J. Mol. Endocrinol. (1995) [Pubmed]
  25. Regulation of the human relaxin genes H1 and H2 by steroid hormones. Garibay-Tupas, J.L., Okazaki, K.J., Tashima, L.S., Yamamoto, S., Bryant-Greenwood, G.D. Mol. Cell. Endocrinol. (2004) [Pubmed]
  26. Biphasic effect of relaxin, inhibitable by a collagenase inhibitor, on the strength of human fetal membranes. Vogel, I., Petersen, A., Petersen, L.K., Helmig, R.B., Oxlund, H., Uldbjerg, N. In Vivo (2004) [Pubmed]
  27. Characteristics of the binding of 32P-labelled human relaxins to the human fetal membranes. Garibay-Tupas, J.L., Maaskant, R.A., Greenwood, F.C., Bryant-Greenwood, G.D. J. Endocrinol. (1995) [Pubmed]
  28. The R273H p53 mutation can facilitate the androgen-independent growth of LNCaP by a mechanism that involves H2 relaxin and its cognate receptor LGR7. Vinall, R.L., Tepper, C.G., Shi, X.B., Xue, L.A., Gandour-Edwards, R., de Vere White, R.W. Oncogene (2006) [Pubmed]
  29. Solution structure and novel insights into the determinants of the receptor specificity of human relaxin-3. Rosengren, K.J., Lin, F., Bathgate, R.A., Tregear, G.W., Daly, N.L., Wade, J.D., Craik, D.J. J. Biol. Chem. (2006) [Pubmed]
  30. The human Leydig insulin-like (hLEY I-L) gene is expressed in the corpus luteum and trophoblast. Tashima, L.S., Hieber, A.D., Greenwood, F.C., Bryant-Greenwood, G.D. J. Clin. Endocrinol. Metab. (1995) [Pubmed]
  31. H2 relaxin overexpression increases in vivo prostate xenograft tumor growth and angiogenesis. Silvertown, J.D., Ng, J., Sato, T., Summerlee, A.J., Medin, J.A. Int. J. Cancer (2006) [Pubmed]
  32. 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-Tupas, J.L., Csiszár, K., Fox, M., Povey, S., Bryant-Greenwood, G.D. J. Mol. Endocrinol. (1999) [Pubmed]
  33. Relaxin and relaxin c-peptide levels in human reproductive tissues. MacLennan, A.H., Grant, P., Borthwick, A.C. Reprod. Fertil. Dev. (1991) [Pubmed]
  34. Adenovirus-mediated expression of human prorelaxin promotes the invasive potential of canine mammary cancer cells. Silvertown, J.D., Geddes, B.J., Summerlee, A.J. Endocrinology (2003) [Pubmed]
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