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A Stephanou
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M Shah
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B Richardson
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S Handwerger
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ABSTRACT

Studies were performed to determine whether ARP-1, which is an orphan receptor of the steroid receptor superfamily, inhibits basal activity of the human placental lactogen (hPL) promoter and the increase in hPL promoter activity in response to the receptors for thyroid hormone (TR) and retinoic acid (RAR). Co-transfection of an ARP-1 expression vector into BeWo choriocarcinoma cells, along with an expression vector containing 1·2 kb of the hPL promoter coupled to a CAT reporter gene, resulted in a dose-dependent inhibition of basal CAT activity. In addition, ARP-1 inhibited the stimulation of CAT activity by RARα and TRβ expression vectors. Mobility shift assays demonstrated that ARP-1 binds specifically to a composite steroid response element on the hPL promoter that confers retinoic acid and T3 responsiveness. The results implicate an inhibitory role for ARP-1 in the regulation of hPL gene expression and strongly suggest that hPL gene expression is regulated, at least in part, by the interaction of stimulatory and inhibitory members of the steroid receptor superfamily.

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A. Stephanou
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N. J. Sarlis
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R. A. Knight
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S. L. Lightman
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H. S. Chowdrey
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ABSTRACT

Adjuvant arthritis (AA) in the rat leads to chronic stimulation of the hypothalamic-pituitary-adrenal (HPA) axis and the loss of its diurnal rhythmicity. We have investigated the effects of adrenalectomy (ADX) and different levels of corticosterone replacement upon plasma ACTH levels and anterior pituitary pro-opiomelanocortin (POMC), GH and prolactin mRNAs during the development of AA. In control ADX animals, we observed the negative feedback effects of exogenous corticosterone on plasma ACTH and anterior pituitary POMC mRNA. In the ADX animal with AA, however, the increased POMC mRNA which was observed was not reduced by exogenous corticosterone on day 7 of AA, although the negative feedback effect of corticosterone on plasma ACTH was intact. On day 14, however, even high dose corticosterone replacement failed to have a significant feedback effect on the raised levels of plasma ACTH.

In control ADX animals, corticosterone replacement resulted in increased anterior pituitary GH mRNA and reduced prolactin mRNA. In contrast, in ADX animals with AA, GH mRNA was reduced and there was a further decrease in prolactin mRNA. In these animals, corticosterone replacement did not affect GH or prolactin mRNA expression.

These data demonstrate a disruption of the normal mechanisms underlying feedback inhibition of the HPA axis by glucocorticoids during AA. Similarly, the glucocorticoid-dependent regulation of GH and prolactin mRNA expression is altered in AA.

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Seán P Barry Medical Molecular Biology Unit, Department of Molecular Haematology, Department of Surgery, Department of Cellular Pathology, School of Biological Sciences, St Bartholomew's and The Royal London School of Medicine and Dentistry, Center for Heart and Vessel Preclinical Studies, Human Genetics Division, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK

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Kevin M Lawrence Medical Molecular Biology Unit, Department of Molecular Haematology, Department of Surgery, Department of Cellular Pathology, School of Biological Sciences, St Bartholomew's and The Royal London School of Medicine and Dentistry, Center for Heart and Vessel Preclinical Studies, Human Genetics Division, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK

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James McCormick Medical Molecular Biology Unit, Department of Molecular Haematology, Department of Surgery, Department of Cellular Pathology, School of Biological Sciences, St Bartholomew's and The Royal London School of Medicine and Dentistry, Center for Heart and Vessel Preclinical Studies, Human Genetics Division, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK

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Surinder M Soond Medical Molecular Biology Unit, Department of Molecular Haematology, Department of Surgery, Department of Cellular Pathology, School of Biological Sciences, St Bartholomew's and The Royal London School of Medicine and Dentistry, Center for Heart and Vessel Preclinical Studies, Human Genetics Division, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK

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Mike Hubank Medical Molecular Biology Unit, Department of Molecular Haematology, Department of Surgery, Department of Cellular Pathology, School of Biological Sciences, St Bartholomew's and The Royal London School of Medicine and Dentistry, Center for Heart and Vessel Preclinical Studies, Human Genetics Division, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK

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Simon Eaton Medical Molecular Biology Unit, Department of Molecular Haematology, Department of Surgery, Department of Cellular Pathology, School of Biological Sciences, St Bartholomew's and The Royal London School of Medicine and Dentistry, Center for Heart and Vessel Preclinical Studies, Human Genetics Division, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK

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Ahila Sivarajah Medical Molecular Biology Unit, Department of Molecular Haematology, Department of Surgery, Department of Cellular Pathology, School of Biological Sciences, St Bartholomew's and The Royal London School of Medicine and Dentistry, Center for Heart and Vessel Preclinical Studies, Human Genetics Division, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK

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Tiziano M Scarabelli Medical Molecular Biology Unit, Department of Molecular Haematology, Department of Surgery, Department of Cellular Pathology, School of Biological Sciences, St Bartholomew's and The Royal London School of Medicine and Dentistry, Center for Heart and Vessel Preclinical Studies, Human Genetics Division, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK

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Richard A Knight Medical Molecular Biology Unit, Department of Molecular Haematology, Department of Surgery, Department of Cellular Pathology, School of Biological Sciences, St Bartholomew's and The Royal London School of Medicine and Dentistry, Center for Heart and Vessel Preclinical Studies, Human Genetics Division, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK

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Christoph Thiemermann Medical Molecular Biology Unit, Department of Molecular Haematology, Department of Surgery, Department of Cellular Pathology, School of Biological Sciences, St Bartholomew's and The Royal London School of Medicine and Dentistry, Center for Heart and Vessel Preclinical Studies, Human Genetics Division, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK

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David S Latchman Medical Molecular Biology Unit, Department of Molecular Haematology, Department of Surgery, Department of Cellular Pathology, School of Biological Sciences, St Bartholomew's and The Royal London School of Medicine and Dentistry, Center for Heart and Vessel Preclinical Studies, Human Genetics Division, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK

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Paul A Townsend Medical Molecular Biology Unit, Department of Molecular Haematology, Department of Surgery, Department of Cellular Pathology, School of Biological Sciences, St Bartholomew's and The Royal London School of Medicine and Dentistry, Center for Heart and Vessel Preclinical Studies, Human Genetics Division, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK

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Anastasis Stephanou Medical Molecular Biology Unit, Department of Molecular Haematology, Department of Surgery, Department of Cellular Pathology, School of Biological Sciences, St Bartholomew's and The Royal London School of Medicine and Dentistry, Center for Heart and Vessel Preclinical Studies, Human Genetics Division, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK

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The urocortin (UCN) hormones UCN1 and UCN2 have been shown previously to confer significant protection against myocardial ischaemia/reperfusion (I/R) injury; however, the molecular mechanisms underlying their action are poorly understood. To further define the transcriptional effect of UCNs that underpins their cardioprotective activity, a microarray analysis was carried out using an in vivo rat coronary occlusion model of I/R injury. Infusion of UCN1 or UCN2 before the onset of reperfusion resulted in the differential regulation of 66 and 141 genes respectively, the majority of which have not been described previously. Functional analysis demonstrated that UCN-regulated genes are involved in a wide range of biological responses, including cell death (e.g. X-linked inhibitor of apoptosis protein), oxidative stress (e.g. nuclear factor erythroid derived 2-related factor 1/nuclear factor erythroid derived 2-like 1) and metabolism (e.g. Prkaa2/AMPK). In addition, both UCN1 and UCN2 were found to modulate the expression of a host of genes involved in G-protein-coupled receptor (GPCR) signalling including Rac2, Gnb1, Dab2ip (AIP1), Ralgds, Rnd3, Rap1a and PKA, thereby revealing previously unrecognised signalling intermediates downstream of CRH receptors. Moreover, several of these GPCR-related genes have been shown previously to be involved in mitogen-activated protein kinase (MAPK) activation, suggesting a link between CRH receptors and induction of MAPKs. In addition, we have shown that both UCN1 and UCN2 significantly reduce free radical damage following myocardial infarction, and comparison of the UCN gene signatures with that of the anti-oxidant tempol revealed a significant overlap. These data uncover novel gene expression changes induced by UCNs, which will serve as a platform to further understand their mechanism of action in normal physiology and cardioprotection.

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