Abstract
Transcriptional regulation of the oxytocin and oxytocin receptor genes underly to a large degree the highly specific and often transient physiologies associated with this peptide hormone system. Using a variety of homologous transcription assays we have endeavoured to identify and characterize the cis and trans elements responsible for the regulation in vivo of the oxytocin peptide gene and the gene for the oxytocin receptor. The bovine ovarian granulosa cell model is a primary culture system where under stimulation by insulin or IGF-I and LH the endogenous oxytocin gene is massively upregulated. We have identified a proximal response element at -160, which in vivo binds the competing nuclear receptors, SF1 and COUP-TF. Additinally ovarian specific transcription factors bind at two additional sites in the distal promoter region. For the bovine oxytocin receptor gene, we have taken advantage of the high endogenous expression of the receptor in the endometrium of the estrous cycle. Using a combination of primary cell culture techniques and in vitro binding of nuclear protein extracts from tissues expressing the receptor in vivo, we have shown there to be a combination of constitutive and inhibitory elements controlling oxytocin receptor gene expression. Similar results were obtained for the human oxytocin receptor gene. At birth there may additionally be a specific stimulatory effect on transcription in the myometrium.
This article is dedicated to Professor Freimut Leidenberger on the occasion of his 60th birthday.
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References
Murphy D, Ho MY 1995 Oxytocin transgenic mice. Adv Exp Med Biol 395: 67–78.
Amico JA, Crowley RS, Insel TR, Thomas A, O’Keefe JA 1995 Effect of gonadal steroids upon hypothalamic oxytocin expression. Adv Exp Med Biol 395: 23–36.
Burbach JPH, Van Tol HHM, Bakkus MHC, Schmale H, Ivell R 1986 Quantitation of vasopressin mRNA and oxytocin mRNA in hypothalamic nuclei by solution hybridization assays. J Neurochem 47: 1814–1821.
Ivell R, Richter D 1984 The gene for the hypothalamic peptide hormone oxytocin is highly expressed in the bovine corpus luteum: biosynthesis, structure and sequence analysis, EMBO J 3: 2351–2354.
Ivell R, Brackett KH, Fields MJ, Richter D 1985 Ovulation triggers oxytocin gene expression in the bovine ovary. FEBS Lett 190: 263–267.
Einspanier A, Ivell R, Rune G, Hodges JK 1994 Oxytocin gene expression in the ovary of the common marmoset monkey Biol Reprod 50: 1216–1222.
Ivell R, Rust W, Einspanier A, Hartung S, Fields M, Fuchs AR 1995 Oxytocin and oxytocin receptor gene expression in the reproductive tract of the pregnant cow: rescue of luteal oxytocin production at term. Biol Reprod 53: 553–560.
Nicholson HD, Jenkin L 1995 Oxytocin and prostatic function. Adv Exp Med Biol 395: 529–538.
Ivell R, Balvers M, Rust W, Bathgate R, Einspanier A 1997 Oxytocin and male reproductive function. Adv Exp Med Biol 424: (in press)
Holtorf AP, Furuya K, Ivell R, McArdle CA 1989 Oxytocin production and oxytocin messenger ribonucleic acid levels in bovine granulosa cells are regulated by insulin and insulin-like growth factor-I: dependence on developmental status of the ovarian follicle. Endocrinology 125: 2612–2620.
McArdle CA, Kohl C, Rieger K, Gröner I, Wehrenberg U 1991 Effects of gonadotropins, insulin and insulin-like growth factor I on ovarian oxytocin and progesterone production. Mol Cell Endocrinol 78: 2I1–220.
Voss AK, Fortune JE 1992 Oxytocin/neurophysin I messenger ribonucleic acid in bovine granulosa cells increases after the luteinizing hormone (LH) surge and is stimulated by LH in vitro. Endocrinology 131: 2755–2762.
Burbach JPH, Adan RAH, Van Tol HHM, Verbeeck MAE, Axelson JF, Van Leeuwen FW, Beekman JM, Ab G 1990 Regulation of the rat oxytocin gene by estradiol. J Neuroendocrinol 2: 633–639.
Adan RAH, Cox JJ, Van Kats JP, Burbach JPH 1992 Thyroid hormone regulates the oxytocin gene. J Biol Chem 267: 1–7.
Adan RAH, Cox JJ, Beischlag TV, Burbach JPH 1993 A composite hormnone response element mediates the transactivation of the rat oxytocin gene by different classes of nuclear hormone receptors. Mol Endocrinol 7: 47–57.
Richard S, Zingg HH 1990 The human oxytocin gene promoter is regulated by estrogens. J Biol Chem 265: 6098–6103.
Richard S, Zingg HH 1991 Identification of a retinoic acid response element in the human oxytocin promoter. J Biol Chem 266: 21428–21433.
Mohr E, Schmitz E 1991 Functional characterization of estrogen and glucoicorticoid responsive elements in the rat oxytocin gene. Mol Brain Res 9: 293–298.
Walther N, Wehrenberg U, Brackmann B, Ivell R 1991 Mapping of the bovine oxytocin gene control region: identification of binding sites for luteal nuclear proteins in the 5’ non-coding region of the gene. J Neuroendocrinol 3: 539–550.
Adan RAH, Walther N, Cox JJ, Ivell R, Burbach JPH 1991 Comparison of the estrogen responsiveness of the rat and bovine oxytocin gene promoters Biochem Biophys Res Commun 175: 117–121.
Wehrenberg U, Ivell R, Jansen M, Von Goedecke S, Walther N 1994 Two orphan receptors binding to a common site are involved in the regulation of the oxytocin gene in the bovine ovary. Proc Natl Acad Sci USA 91: 1440–1444.
Wehrenberg U, Von Goedecke S, IveII R, Walther N 1994 The orphan receptor SF-1 binds to the COUP-like element in the promoter of the actively transcribed oxytocin gene. J Neuroendocrinol 6: 1–4.
Bakke M, Lund J 1995 Mutually exclusive interactions of two nuclear orphan receptors determine activity of a cyclic adenosine 3’,5’-monophosphate-responsive sequence in the bovine CYP17 gene. Mol Endocrinol 9: 327–339.
Leers-Suchetat S, Morohashi KI, Mason JI, Melner MH 1997 Synergistic activation of the human type II 313-hydroxysteroid dehydrogenase/D5-D4 isomerase promoter by the transcription factor steroidogenic factor 1/Adrenal 4-binding protein and phorbol ester. J Biol Chem 272: 7960–7967.
Lala DS, Syka PM, Lazarchik SB, Mangelsdorf DJ, Parker KL, Heyman RA 1997 Activation of the orphan nuclear receptor steroidogenic factor 1 by oxysterols. Proc Natl Acad. Sci USA 94: 4895–4900.
Kascheike B, Ivell R, Walther N 1997 Alterations in the chromatin structure of the distal promoter region of the bovine oxytocin gene correlate with ovarian expression. DNA Cell Biol 16: (in press).
Kascheike B, Nell R, Jansen M, Walther N 1995 Regulation of the oxytocin promoter: orphan receptors and other factors. In: Saito T, Kurokawa K, Yoshida S (eds) Neurohypophysis: Recent Progress of vasopressin and Oxytocin Research. Elsevier Science, Amsterdam, pp 165–174.
Ivell R, Russell JA 1995 (eds) Oxytocin, Cellular and Molecular Approaches in Medicine and Research. Plenum Press, New York.
Bale TL, Dorsa DM 1995 Sex differences in and effects of estrogen on oxytocin receptor messenger ribonucleic acid expression in the ventromedial hypothalamus. Endocrinology 136: 27–32.
Ostrowski NL, Lolait SJ 1995 Oxytocin receptor gene expression in female raiey: the effect of estro-gen. Adv Exp Med Biol 395: 329–340.
Fuchs AR, Fields MJ, Freidman S, Shemesh M, Ivell R 1995 Oxytocin and the timing of parturition: influence of oxytocin receptor gene expression, oxytocin secretion, and oxytocin induced prostaglandin Fla and E2 release. Adv Exp Med Biol 395: 405–420.
Parry LJ, Bathgate RAD, Shaw G, Renfree MB, Ivell R 1997 Evidence for a local fetal influence on myometrial oxytocin receptors during pregnancy in the tammar wallaby (Macropus eugenii). Biol Reprod 56: 200–207.
Sheldrick EL, Flick-Smith HC, Dos santis Cruz GJ 1993 Oxytocin receptor binding activity in cultured ovine endometrium. J Reprod Fertil 98: 521–528.
Horn S, Bathgate R, Lioutas C, Bracken K, Ivell R 1997 Bovine endometrial epithelial cells as a model system to study oxytocin receptor regulation. Hum Reprod (in press).
Bazer FW, Johnson HM 1991 Type I conceptus interferons: maternal recognition of pregnancy signals and potential therapeutic agents. Am J Reprod Immunol 26: 19–22.
Flint APF 1995 Interferon, the oxytocin receptor and the maternal recognition of pregnancy in ruminants and non-ruminants: a comparative approach. Reprod Fertil Devel 7: 313–318.
Abayasekara DRE, Sheldrick EL, Flick-Smith HC, Flint APF 1995 Role of protein kinase C in the inhibitory action of trophoblast interferons on expression of the oxytocin receptor in sheep endometrium. Endocrine 3: 151–158.
Phaneuf S, Asboth G, Carrasco MP, Europe-Finner GN, Saji F, Kimura T, Harris A. Lopez-Bernal A 1997 The desensitization of oxytocin receptors in human myometrial cells is accompanied by down-regulation of oxytocin receptor messenger RNA. J Endocrinol 154: 7–18.
Bathgate R, Rust W, Salvers M, Hartung S, Morley S, Ivell R 1995 Structure and expression of the bovine oxytocin receptor gene. DNA Cell Biol 14: 1037–1048.
Inoue T, Kimura T, Azuma C, Inazawa J, Takemura M, Kikuchi T, Kubota Y, Ogita K, Saji F 1994 Structural organization of the human oxytocin receptor gene. J Biol Chem 269: 32451–32456.
Kubota Y, Kimura T, Hashimoto K, Tokugawa Y, Nobunaga K, Azuma C, Saji F, Murata Y 1996 Structure and expression of the mouse oxytocin receptor gene. Mol Cell Endocrinol 124: 25–32.
Rozen F, Russo C, Banville D, Zingg HH 1995 Structure, characterization and expression of the rat oxytocin receptor gene. Proc Natl Acad Sci USA 92: 200–204.
Ivell R, Bathgate R, Kimura T, Parry L 1997 Molecular biology of the oxytocin receptor: a comparative approach. Trans Biochem Soc 25: 979–987.
Bale TL, Dorsa DM 1997 Cloning, novel promoter sequence, and estrogen regulation of a rat oxytocin receptor gene. Endocrinology 138: 1151–1158.
Hoare S, Wood TG, Copland JA, Acosta M, Jeng YJ, Izban MG, Soloff MS 1997 Characterization of the human oxytocin receptor gene promoter. Abstract P3–551, Endocrine Society Annual Meeting, Minneapolis, 1997.
Grazzini E, Russo C, Rozen F, Zingg HH 1997 Activation of the rat oxytocin receptor gene promoter. Abstract P3–553, Endocrine Society Annual Meeting, Minneapolis, 1997.
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Ivell, R., Bathgate, R.A., Walther, N., Kimura, T. (1998). The Molecular Basis of Oxytocin and Oxytocin Receptor Gene Expression in Reproductive Tissues. In: Zingg, H.H., Bourque, C.W., Bichet, D.G. (eds) Vasopressin and Oxytocin. Advances in Experimental Medicine and Biology, vol 449. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4871-3_37
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DOI: https://doi.org/10.1007/978-1-4615-4871-3_37
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