The Tissue‐Specific Processing of Pro‐Opiomelanocortin

Abstract

In 1967, a new era in endocrinology was born. A set of pulse chase experiments performed by Steiner and Oyer (1) elegantly showed, for the first time, that insulin was derived from a larger precursor molecule, proinsulin. The radical revelation, that bioactive peptides are derived from larger precursors, forever changed endocrinology and, from then on, the concept of hormone precursors (or prohormones) has become a central dogma. Subsequently, the use of both traditional protein sequence studies and recombinant DNA technology have provided definitive structures for the precursors of all the known bioactive peptides as well as identifying several previously unknown precursors, the function of which are still not fully understood. In general, all these molecules contain within their sequence one or more copies of the active peptide while some contain several different bioactive peptides. In addition, they undergo a series of highly regulated post-translational events that includes specific proteolytic cleavage and modifications such as amidation, acetylation and phophorylation. These post-translational processing events are especially interesting because there are a number of examples where the extent of processing can yield very different bioactive peptides from the same precursor. Probably the best example of this phenomenon, and arguably the most studied prohormone, is the ACTH precursor pro-opiomelanocortin (POMC). This short review aims to highlight why it has been of such interest to (neuro)endocrinologists and suggests that it still has a few more secrets to yield. Discovery of POMCThe discovery of POMC ( Fig. 1) was preceded by a number of what, at the time, appeared to be unrelated observations. Both ACTH and a-melanocyte-stimulating hormone (a-MSH) had been purified and sequenced from the pituitaries of various species. However, the fact that a-MSH has the same amino acid sequence as the first 13 residues of ACTH was not seen to be of much significance until the isolation of corticotrophin-like intermediate peptide (CLIP) (2), the peptide that comprises the C-terminal of ACTH. This, together with the identification of larger molecular weight forms of immunoreactive ACTH (3, 4), began to suggest that ACTH and a-MSH were indeed derived from the same molecule.A further observation suggesting the existence of a common precursor to a number of pituitary hormones was that the sequence of the newly-discovered pituitary peptide, b-endorphin (5, 6), which had strong opiate-like activity, shared the same sequence as the C-terminal of b-lipotrophin (b-LPH), another pituitary hormone released under the same conditions as ACTH. It was subsequently shown that b-LPH was expressed in the same pituitary cells as a-MSH and CLIP (7).In 1976, the first published report came that suggested ACTH and b-LPH were derived from the same molecule (8) It is just over 30 years since the definitive identification of the adrenocorticotrophin (ACTH) precursor, pro-opiomelanocotin (POMC). Although first characterised in the anterior and...

In vivo alternative assessment of the chemicals that interfere with anterior pituitary POMC expression and interrenal steroidogenesis in POMC: EGFP transgenic zebrafish

“…As with the 'tissue-specific processing' of endogenous POMC suggested in rodents (Bicknell, 2008), the anterior domain of the pituitary gland is also the key compartment of POMC-expressing cells involved in the production of ACTH and functional regulation of zebrafish interrenal steroidogenesis . Our results have confirmed that the promoter selected for the regulation elements in this transgenic line contains the proper region for reporting endogenous anterior pituitary POMC mRNA expression (Fig.…”

“…The POMC gene encodes a polypeptide precursor that undergoes extensive, "tissue-specific" posttranslational modification to generate a range of smaller and biologically active peptides, including adrenocorticotropin (ACTH) and α-, β-, γ-melanocyte-stimulating hormone. For instance, the processing of POMC in anterior pituitary corticotrophs results in the generation of pro-γ-MSH, ACTH, and β-LPH (Bicknell, 2008). These POMC-derived hormones regulate many physiological processes including steroidogenesis, skin pigmentation, food intake, and energy balance (Coll et al, 2004(Coll et al, , 2005Coll and Tung, 2009).…”

60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH

“…ACTH is mainly produced in the corticotropic cells from the anterior pituitary, but is also produced in the brain, adrenal medulla, skin, and placenta (Vrezas et al 2003, Bicknell 2008, Evans et al 2012. As ACTH is the most potent stimulus of the adrenal cortex, most of the knowledge on its mechanism of action derives from studies on the adrenal cortex or ACTH receptor-expressing cells.…”

MALDI mass spectrometry imaging analysis of pituitary adenomas for near-real-time tumor delineation

“…The ACTH-related pituitary hormones are processing products of a common precursor protein named pro-opiomelanocortin (POMC). Enzymatic cleavage of this prohormone produces the following peptides: signal peptide, N-terminal glycopeptide, γ-melanocyte-stimulating hormone (γ-MSH), joining peptide, ACTH, α-melanocyte-stimulating hormone (α-MSH), corticotropinlike intermediate peptide (CLIP), β-lipotropin (β-LPH), γ-lipotropin (γ-LPH), and β-endorphin (16).…”