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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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The melanocortin 2 receptor accessory protein (MRAP) was originally discovered to be an essential co-receptor for the ACTH receptor/melanocortin 2 receptor, and it physically interacts with this receptor and is required for receptor trafficking and ligand binding. A related molecule, MRAP2, is mainly expressed in the CNS and appears to have a role with the melanocortin 4 receptor. Consistent with this is the observation that a massively obese phenotype develops when the Mrap2 gene is deleted in mice. However, the characteristics of this phenotype differ from those of Mc4r-deleted mice and suggest that an additional role, possibly resulting from an interaction with other receptors is possible. In support of this, a functional interaction with the prokineticin receptors was recently reported. Evidence for other receptor interactions and aspects of the tissue distribution of MRAP and MRAP2 gene expression may indicate that these accessory proteins have a wider role than with the melanocortin receptors alone.
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Angiotensin II acts through two pharmacologically distinct receptors known as AT1 and AT2. Duplication of the AT1 receptor in rodents into At1a and b subtypes allows tissue-specific expression of the AT1b in adrenal and pituitary tissue. Adrenal expression of this receptor is increased in the offspring of rat mothers exposed to a low-protein diet and this is associated with the undermethylation of its promoter. This phenomenon is blocked by the inhibition of maternal glucocorticoid synthesis by metyrapone. We have mapped the transcriptional start site of the promoter and demonstrated that a 1.2 kbp fragment upsteam of this site is effective in driving luciferase expression in mouse Y1 cells. A combination of bioinformatic analysis, electrophoretic mobility shift analysis (EMSA), and mutagenesis studies demonstrates: i) the presence of a putative TATA box and CAAT box; ii) the presence of three Sp1 response elements, capable of binding SP1; mutation of any pair of these sites effectively disables this promoter; iii) the presence of four potential glucocorticoid response elements which each bind glucocorticoid receptor in EMSA, although only two confer dexamethasone inhibition on the promoter; iv) the presence of two AP1 sites. Mutagenesis of the distal AP1 site greatly diminishes promoter function but this is also associated with the loss of dexamethasone inhibition. These studies will facilitate an understanding of the mechanisms by which fetal programming leads to long term alterations in gene expression and the development of adult disease.
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The ACTH receptor melanocortin 2 receptor (MC2-R) is a G-protein-coupled receptor principally expressed in the adrenal cortex and the adipocyte, where it stimulates steroidogenesis and lipolysis respectively. The coding region of the murine gene is encoded by a single exon, although three upstream non-coding exons have been documented, one of which is incorporated by alternative splicing in adrenal cells. We have detected a novel transcript in adipocytes, which includes a previously unidentified 86 bp exon upstream of the coding region. This transcript appears with slower kinetics during a time course of differentiation of 3T3-L1 cells and is much more highly expressed in these cells and murine adipose tissues than in the Y1 murine adrenocortical cell line, also it is undetectable in murine foetal testes. Inclusion of this exon extends the 5′ UTR to 468 bp and introduces three upstream open reading frames. These are typical features of mRNAs under translational control and imply that the MC2-R gene is regulated both transcriptionally and post-transcriptionally during adipogenesis.
