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The cloning of the bovine proopiomelanocortin (POMC) cDNA in 1978 by Nakanishi and colleagues was the result of a remarkable series of exacting and ingenious experiments. With this work, they instantly confirmed the single precursor hypothesis for adrenocorticotrophic hormone-β-lipotropin, as it was then known, and in so doing revealed the existence of additional, largely unpredicted, N-terminal peptides that together formed the POMC precursor peptide. This work paved the way for a host of additional studies into the physiology of these peptides and their regulation. Furthermore, the cloning of the murine Pomc gene was essential for subsequent studies, in which Pomc was intentionally deleted in the mouse illuminating its substantial role in body weight regulation and adrenal function. Contemporaneously with this work, naturally occurring mutations in human POMC came to light underlining the vital role of this gene in appetite regulation. This article reviews each of these aspects of POMC with the benefit of several decades of hindsight and informed by more recent genomic and transcriptomic data.
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In this study, we report the cDNA cloning of hamster adrenal steroidogenic acute regulatory (StAR) protein and the effect of adrenocorticotrophin (ACTH) on its expression in vivo. A hamster adrenal cDNA library was screened using an 852 bp fragment obtained by polymerase chain reaction; this fragment corresponds to the entire coding sequence (CDS) of the hamster adrenal StAR cDNA. Ten clones of different lengths were isolated and sequenced. The longest clone was 1564 bp and contained 34 bp in the 5'-untranslated region, 852 bp in the CDS, and 678 bp in the 3'-untranslated region (3'-UTR). Two polyadenylation signal sequences were found in the 3'-UTR. The CDS of the ten isolated clones was identical, but six of these lacked the last 132 nucleotides in the 3'-UTR, thus indicating that they had used the first polyadenylation signal. The hamster StAR protein contains 284 amino acid residues, and is 91.9% homologous to mouse, 90.5% to rat, 86.4% to human, 85% to porcine, and 82.5% to bovine StAR protein. Southern blot analysis indicated the presence of only one StAR gene in the hamster genome. Northern blotting analysis revealed the presence of the StAR mRNA in male and female steroidogenic tissues, namely adrenals and gonads, but not in the liver or in the kidneys of either sex. Three mRNA species of 1.7, 3.1 and 5.3 kb were found in whole hamster adrenals. Administration of ACTH to hamsters provoked increases (two- to threefold) in the adrenal content of the StAR mRNA within 1 h in vivo. Western blotting analysis on adrenal mitochondria showed that the level of StAR protein was also significantly elevated (1.5-fold) 1 h after ACTH treatment.
INSERM EMI 01-05, Department of Cellular Responses and Dynamics, CEA, Grenoble, France
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INSERM EMI 01-05, Department of Cellular Responses and Dynamics, CEA, Grenoble, France
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INSERM EMI 01-05, Department of Cellular Responses and Dynamics, CEA, Grenoble, France
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INSERM EMI 01-05, Department of Cellular Responses and Dynamics, CEA, Grenoble, France
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INSERM EMI 01-05, Department of Cellular Responses and Dynamics, CEA, Grenoble, France
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INSERM EMI 01-05, Department of Cellular Responses and Dynamics, CEA, Grenoble, France
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INSERM EMI 01-05, Department of Cellular Responses and Dynamics, CEA, Grenoble, France
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INSERM EMI 01-05, Department of Cellular Responses and Dynamics, CEA, Grenoble, France
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hypothalamic pathology ( Oelkers et al. 1992 , Mayenknecht et al. 1998 ). The pituitary adrenocorticotrophin hormone (ACTH) is the major trophic factor regulating and maintaining adrenocortical function, affecting such diverse processes as steroidogenesis
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The main regulators of aldosterone secretion in adrenal gland zona glomerulosa (ZG) cells are the hormones angiotensin II (Ang II) and adrenocorticotrophin (ACTH) and small increases in the extracellular potassium (K(+)) concentration. The action of these agonists is mediated by different signalling systems - ACTH is mediated by cAMP and activation of protein kinase A while Ang II and K(+) activate two protein kinases, Ca(2+)-calmodulin-dependent protein kinase (CamK) and diacylglycerol-dependent protein kinase (PKC). Ang II, besides being one of the main agonists for the secretion of aldosterone, also stimulates proliferation of ZG cells, a process mediated by mitogen-activated protein kinases (MAPKs). Recent studies aimed at elucidating the molecular mechanisms underlying cell proliferation have shown that calcineurin is the principal regulator of MAPKs activity. The purpose of this review is to discuss experimental evidence of possible reciprocal influences between the signalling pathways regulating proliferation and steroidogenesis in ZG cells.
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INTRODUCTION
In 1980, studies of the hormone regulation of adrenocortical steroidogenesis had reached a turning point. The important differences in function and responsiveness of the different adrenocortical zones had been recognized (Tait, Tait & Bell, 1980; see also Brown, 1982), and the need for purified cell populations from each zone for in-vitro studies emphasized. Two reviews of that year (Schimmer, 1980; Tait et al. 1980) also highlighted advances which had been made in understanding the mechanisms of hormone-stimulated (particularly adrenocorticotrophin (ACTH)-stimulated) cyclic AMP (cAMP) generation in the adrenal cortex, and how cAMP could bring about an increase in adrenal steroidogenesis. However, these reviews also stressed that not all the known steroidogenic agonists stimulated cAMP production. At least one agonist (angiotensin II (AII)) operated through a mechanism requiring an increase in intracellular Ca2+ concentration ([Ca2+]i).
In many other tissues, agonists such as AII, vasopressin and acetylcholine were known
Department of Obstetrics and Gynaecology, St George’s Hospital, London SW17 0QT, UK
Bruker Daltonics Limited, Coventry CV4 9GH, UK
National Institute for Medical Research, Mill Hill, London NW7 1AA, UK
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Department of Obstetrics and Gynaecology, St George’s Hospital, London SW17 0QT, UK
Bruker Daltonics Limited, Coventry CV4 9GH, UK
National Institute for Medical Research, Mill Hill, London NW7 1AA, UK
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Department of Obstetrics and Gynaecology, St George’s Hospital, London SW17 0QT, UK
Bruker Daltonics Limited, Coventry CV4 9GH, UK
National Institute for Medical Research, Mill Hill, London NW7 1AA, UK
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Department of Obstetrics and Gynaecology, St George’s Hospital, London SW17 0QT, UK
Bruker Daltonics Limited, Coventry CV4 9GH, UK
National Institute for Medical Research, Mill Hill, London NW7 1AA, UK
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Department of Obstetrics and Gynaecology, St George’s Hospital, London SW17 0QT, UK
Bruker Daltonics Limited, Coventry CV4 9GH, UK
National Institute for Medical Research, Mill Hill, London NW7 1AA, UK
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Department of Obstetrics and Gynaecology, St George’s Hospital, London SW17 0QT, UK
Bruker Daltonics Limited, Coventry CV4 9GH, UK
National Institute for Medical Research, Mill Hill, London NW7 1AA, UK
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Department of Obstetrics and Gynaecology, St George’s Hospital, London SW17 0QT, UK
Bruker Daltonics Limited, Coventry CV4 9GH, UK
National Institute for Medical Research, Mill Hill, London NW7 1AA, UK
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Department of Obstetrics and Gynaecology, St George’s Hospital, London SW17 0QT, UK
Bruker Daltonics Limited, Coventry CV4 9GH, UK
National Institute for Medical Research, Mill Hill, London NW7 1AA, UK
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Placental neurokinin B appears to be post-translationally modified by phosphocholine (PC) attached to the aspartyl side chain at residue 4 of the mature peptide. Corticotrophin releasing factor (CRF) was found to be expressed by the rat placenta with the main secreted forms being phosphocholinated proCRF+/− one or two polysaccharide moieties. A combination of high-pressure liquid chromatography (HPLC) and two-site immunometric analysis suggested that PC was also attached to the placental precursors of adrenocorticotrophin, hemokinin, activin and follistatin. However, the fully processed forms of rat placental activin and CRF were free of PC. Formerly, the parasitic filarial nematodes have used PC as a post-translational modification, attached via the polysaccharide moiety of certain secretory glycoproteins to attenuate the host immune system allowing parasite survival, but it is the PC group itself which endows the carrier with the biological activity. The fact that treatment of proCRF peptides with phospholipase C but not endoglycosidase destroyed PC immunoreactivity suggested a simpler mode of attachment of PC to placental peptides than that used by nematodes. Thus, it is possible that by analogy the placenta uses its secreted phosphocholinated hormones to modulate the mother’s immune system and help protect the placenta from rejection.
Department of Psychiatry, University of Florida, Gainesville, Florida, USA
Department of Molecular Cell Physiology, Free University, Amsterdam, The Netherlands
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Department of Psychiatry, University of Florida, Gainesville, Florida, USA
Department of Molecular Cell Physiology, Free University, Amsterdam, The Netherlands
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Department of Psychiatry, University of Florida, Gainesville, Florida, USA
Department of Molecular Cell Physiology, Free University, Amsterdam, The Netherlands
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Department of Psychiatry, University of Florida, Gainesville, Florida, USA
Department of Molecular Cell Physiology, Free University, Amsterdam, The Netherlands
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Department of Psychiatry, University of Florida, Gainesville, Florida, USA
Department of Molecular Cell Physiology, Free University, Amsterdam, The Netherlands
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=15 min (just after the stressful event) and t =120 min (just before they were killed). From these samples, plasma adrenocorticotrophin (ACTH) and corticosterone levels were determined by means of an RIA ( Von Frijtag et al. 1998 ). Two hours after
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Hunyady L Clark AJ 2002 Failed export of the adrenocorticotrophin receptor from the endoplasmic reticulum in non-adrenal cells: evidence in support of a requirement for a specific adrenal accessory factor . Journal of Endocrinology 174 17
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level of the steroidogenic acute regulatory (StAR) protein mRNA in hamster adrenals . Endocrine Research 22 515 – 520 . Fleury A Ducharme L LeHoux JG 1998 In vivo effects of adrenocorticotrophin on the expression of the hamster
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isolation and amino acid sequence of an adrenocorticotrophin from the pars distalis of a corticotrophin-like intermediate lobe peptide from the neurointermediate lobe of the pituitary of the dogfish (Squalus acanthias) . Biochemical Journal 141 427
