Disease relevance of POMC

• Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans [1].
• Human POMC DNA probe hybridized with only a single size class of RNA (approximately 1,200 nucleotides) from the adenoma and nonadenoma cells of each patient [2].
• The effects of corticotropin-releasing hormone (CRH) and dexamethasone on proopiomelanocortin (POMC) mRNA levels in cultured pituitary adenoma cells were studied in 10 patients with Cushing's disease [2].
• PMA increased POMC mRNA levels only in carcinoid cells [3].
• In contrast with the V3 receptor, CRH receptor mRNA was detected in the majority of neuroendocrine tumors irrespective of their POMC status [4].
• Molecular genetic abnormalities of POMC should always be considered in patients with early onset adrenal insufficiency and obesity, even in the presence of normal pigmentation and multiple pituitary hormone anomalies [5].

Psychiatry related information on POMC

• Psychologic stress increases plasma levels of prolactin, cortisol, and POMC-derived peptides in man [6].
• Finally, an awareness of possible genetic causes of eating disorders will help determine the causes--and thus the treatments--in children and adolescents with eating disorders, as exemplified by obese patients with mutations in the POMC, PC1, leptin, and MC4R loci [7].
• Hexarelin decreases slow-wave sleep and stimulates the secretion of GH, ACTH, cortisol and prolactin during sleep in healthy volunteers [8].
• Nocturnal ghrelin, ACTH, GH and cortisol secretion after sleep deprivation in humans [9].
• Lack of effect of desmopressin on ACTH and cortisol responses to ovine corticotropin-releasing hormone in anorexia nervosa [10].

High impact information on POMC

• The most important positive regulator of melanogenesis is the MC1 receptor with its ligands melanocortins and ACTH, whereas among the negative regulators agouti protein stands out, determining intensity of melanogenesis and also the type of melanin synthesized [11].
• Hence, cutaneous expression of the CRH/POMC system is highly organized, encoding mediators and receptors similar to the hypothalamic-pituitary-adrenal (HPA) axis [12].
• Familial glucocorticoid deficiency (FGD), or hereditary unresponsiveness to adrenocorticotropin (ACTH; OMIM 202200), is an autosomal recessive disorder resulting from resistance to the action of ACTH on the adrenal cortex, which stimulates glucocorticoid production [13].
• The peak on chromosome 2 coincided with the region containing the gene (POMC) encoding pro-opiomelanocortin, a locus previously linked to leptin levels and fat mass in a Mexican-American population and shown to be mutated in obese humans [14].
• ACTH and cortisol levels during residency training [15].

Chemical compound and disease context of POMC

• Dex decreases ACTH release and POMC mRNA levels in some bronchial carcinoids [3].
• This nodule was removed surgically after preparation of the patient by a 1-month treatment with octreotide: the tumor proved to be a typical bronchial carcinoid, containing extremely high concentrations of immunoreactive ACTH (198 pmol/mg wet wt tissue) and POMC messenger RNA by Northern blot [16].
• The present results indicate that POMC-derived pituitary peptides other than ACTH are unlikely to participate in the aldosterone secretion in normal subjects or in patients with primary aldosteronism [17].
• The pituitary V3 vasopressin receptor and the corticotroph phenotype in ectopic ACTH syndrome [4].
• Angiotensins I and II stimulated ACTH secretion from both adenomas and nonadenomatous tissues, while angiotensin I-induced ACTH secretion was inhibited by angiotensin-converting enzyme inhibitor [18].

Biological context of POMC

• The powerful effects of POMC peptides and probably CRH on the skin pigmentary, immune, and adnexal systems are consistent with stress-neutralizing activity addressed at maintaining skin integrity to restrict disruptions of internal homeostasis [12].
• Apart from its role in the onset of drive to eat, the circadian patterns of gene expression of NPY, GAL, and POMC denote independent control of the timing device on the synthesis and availability for release of orexigenic signals [19].
• The transfected rat POMC promoter -706/+64, fused to the luciferase reporter gene, was induced by LIF, which exerted strong (18-fold) synergy with CRH [20].
• Using this procedure, we assigned to specific chromosome sites three cloned genes and one DNA polymorphism: amylase gene (AMY) to 1p21; proopiomelanocortin gene (POMC) to 2p23, somatostatin gene (SST) to 3q28, and a single copy DNA segment (D3S1) to 3q12 [21].
• A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism [22].

Anatomical context of POMC

• Here we report that estradiol (E2) triggers a robust increase in the number of excitatory inputs to POMC neurons in the arcuate nucleus of wild-type rats and mice [23].
• Expression of the pro-opiomelanocortin (POMC) gene was examined in normal human lymphocytes and lymphocyte cell lines infected by lymphotropic viruses [24].
• POMC gene transcripts were detected in human lymphocytes using stringent RNA-RNA hybridizations [24].
• These data show that genetic variants at the POMC locus influence body fat distribution within the normal range, suggesting a novel role for POMC in metabolic regulation [25].
• The transcript levels in an EBV-transformed B lymphocyte line were not affected by dexamethasone or corticotropin-releasing hormone, known regulators of anterior pituitary POMC gene expression [24].

Associations of POMC with chemical compounds

• In turn, cortisol has well defined actions on surfactant biosynthesis and consequently fetal lung maturation, as well as effects on placental CRH/POMC release, which may be important to the initiation of labor [26].
• The size of POMC mRNA did not change through the culture or after incubation with CRH or dexamethasone [2].
• This important secretory product of POMC was shown to possess an interesting aldosterone-stimulating activity on a human adrenal aldosteronoma [27].
• Beta-TC3 cells transfected with the mutant POMC cDNA produced a mutant beta-MSH/beta-endorphin fusion protein [22].
• A critical transcription factor responsible for POMC overproduction was identified as Nur77, a member of the orphan steroid receptor superfamily [28].
• Stimulation with alpha-MSH increased the levels of intracellular cAMP, but not Ca(2+), in chondrocytes [29].

Physical interactions of POMC

• However, ACTH1-17 is not the only POMC peptide in the skin and may interact with related peptides at the MC-1 receptor [30].
• Three transcription factors have been identified that affect transcription of the POMC gene by binding to two different sites within the CRH-responsive element of that promoter [31].
• Their effects are mediated via different protein G-coupled melanocortin (MC) receptors that are capable to bind one or more POMC-derived peptides [32].
• In vitro studies using the rat POMC promoter suggested that binding of the glucocorticoid receptor complex to a -63 bp binding site is correlated with repression of POMC gene transcription, and that specific mutations in this region abolish this effect [33].
• Regulation of ACTH receptor mRNA and binding sites by ACTH and angiotensin II in cultured human and bovine adrenal fasciculata cells [34].

Enzymatic interactions of POMC

• Plasma leptin levels were not affected by CRH infusion in either the controls or the patients despite clear-cut elevations in plasma ACTH and cortisol [35].

Co-localisations of POMC

• GAL is colocalized with corticotropin (ACTH) in the human pituitary and with epinephrine (E) and norepinephrine (NE) in chromaffin cells of the adrenal medulla [36].

Regulatory relationships of POMC

• Another multihormonal cell may function during cold stress to release both ACTH and thyroid-stimulating hormone (TSH) under the influence of AVP [37].
• CRH-induced ACTH secretion from the cultured adenoma cells was also abolished in Na(+)-free extracellular solution, but not in tetrodotoxin-containing extracellular solution [38].
• In vivo and in vitro studies have shown that expression of ACTH-R is upregulated by its own ligand ACTH in several species [39].
• We have now directly assessed the action of BMP signaling on POMC expression and found that BMP4 represses POMC mRNA levels and promoter activity [40].
• AGRP significantly enhanced the ACTH (P < 0.05) response to IL-1 beta [41].

Other interactions of POMC

• Because expression of, for example, the MC1 receptor is stimulated in a similar dose-dependent manner by UVR, cytokines, MSH peptides or melanin precursors, actions of the ligand peptides represent a stochastic (predictable) nonspecific response to environmental/endogenous stresses [12].
• AVP or angiotensin II (A-II), or their activated second messengers, also increase percentages of cells that bind CRH and store ACTH [37].
• SUMMARY BACKGROUND DATA: ACTH increases adrenal cell growth and steroidogenesis by means of ACTH-R [39].
• LH, FSH, PRL, ACTH, and cortisol were determined every 15 min for 180 min [42].
• On the other hand, in obesity ghrelin shows preserved influence on PRL, ACTH, and insulin secretion as well as in glucose levels [43].

Analytical, diagnostic and therapeutic context of POMC

• Human POMC mRNA in the cells was analyzed by Northern blot hybridization [2].
• Isolation of tumor cells by the novel technique of laser capture microdissection and subsequent RT-PCR showed expression of POMC messenger ribonucleic acid and cytochrome p450 enzyme messenger ribonucleic acid within the same cells [44].
• In situ hybridization, using a complementary DNA probe, revealed POMC messenger ribonucleic acid in a subpopulation of tumor cells [45].
• RESULTS: The intercontraction interval was decreased after intravesical instillation of acetic acid (73.1% or 68.1% decrease) in 2 control groups treated with saline or the gene gun without POMC cDNA, respectively [46].
• Using cross-linking and gel filtration techniques, we demonstrated that POMC forms oligomers at both neutral and acidic pHs and calcium was not necessary. delta N-POMC, which lacks the N-terminal sorting signal for the regulated secretory pathway, also formed similar oligomers, indicating that the sorting and oligomerization domains are different [47].

References