60 YEARS OF POMC: The proopiomelanocortin gene: discovery, deletion and disease

Abstract

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.

POMC: The Physiological Power of Hormone Processing

“…The same year, cloning cDNA from pituitary pars intermedia provided the gene sequence for bovine POMC (265) which was independently confirmed by protein sequencing (264). Similar approaches identified the sequences for the human (72,391), mouse (407), rat (105), and pig (38) genes (69). Despite the sequence being highly conserved, there is some variation in the lengths of some of the peptides in different species (FIGURE 2).…”

“…Many of these studies were carried out using techniques such as Northern blot and PCR and show expression, but not whether translation to the protein or processing occurs in these locations. In fact, it has been shown that many of these tissues contain a shorter mRNA transcript that would not be translated and therefore no peptide produced (69). Furthermore, in both humans and murine mod-recombination in regions including the hippocampus, regions of the cortex, and midbrain (284).…”

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

“…We (Kilianova et al 2006, Roy et al 2007 and others have been able to decipher the mechanisms of expression and regulation of MC2R in melanocortin-2 receptor accessory proteins (MRAPs) expressing cells. The role of MRAP1 as well as the relative roles that the various forms of MRAPs identified thereafter has been documented in several recent reviews (Hinkle & Sebag 2009, Cooray & Clark 2011, Jackson et al 2015, Clark 2016. Another particularity is that ACTH treatment of adrenocortical cells (4 h or more) increases the expression of MC2R (Penhoat et al 1989, Mountjoy et al 1994), as well as the level of MRAP and MRAP2 (Hofland et al 2012).…”

60 YEARS OF POMC: POMC: the consummate peptide hormone precursor

“…Confirmation of the single-precursor concept was provided by the cloning of the POMC gene by Nakanishi and coworkers; work reviewed by Adrian Clark (Clark 2016). Cloning of POMC additionally revealed undiscovered N-terminal components of this precursor whose potential biological function is reviewed by Andrew Bicknell (Bicknell 2016).…”