UNIPROT:P01189 - FACTA Search

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Query: UNIPROT:P01189 (beta-endorphin)
21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Newly synthesized prohormones and their processing enzymes transit through the same compartments before being packaged into regulated secretory granules. Despite this coordinated intracellular transport, prohormone processing does not occur until late in the secretory pathway. In the mouse pituitary AtT-20 cell line, conversion of pro-opiomelanocortin (POMC) to mature adrenocorticotropic hormone involves the prohormone convertase PC1. The mechanism by which this proteolytic processing is restricted to late secretory compartments is unknown; PC1 activity could be regulated by compartment-specific activators/inhibitors, or through changes in the ionic milieu that influence its activity. By arresting transport in a semi-intact cell system, we have addressed whether metabolically labeled POMC trapped in early secretory compartments can be induced to undergo conversion if the ionic milieu in these compartments is experimentally manipulated. Prolonged incubation of labeled POMC trapped in the endoplasmic reticulum or Golgi/trans-Golgi network did not result in processing, thereby supporting the theory that processing is normally a post-Golgi/trans-Golgi network event. However, acidification of these compartments allowed effective processing of POMC to the intermediate and mature forms. The observed processing increased sharply at a pH below 6.0 and required millimolar calcium, regardless of the compartment in which labeled POMC resided. These conditions also resulted in the coordinate conversion of PC1 from the 84/87 kDa into the 74-kDa and 66-kDa forms. We propose that POMC processing is predominantly restricted to acidifying secretory granules, and that a change in pH within these granules is both necessary and sufficient to activate POMC processing.
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PMID:Ionic milieu controls the compartment-specific activation of pro-opiomelanocortin processing in AtT-20 cells. 857 86

RESP18 (regulated endocrine-specific protein of 18 KD) is an endoplasmic reticulum (ER) protein that was identified by coordinate dopaminergic regulation with pro-opiomelanocortin in the rat neurointermediate pituitary. Many attributes of RESP18 suggest an important function in neuroendocrine cells. Several neuropeptides, growth factors, and enzymes involved in biosynthesis of classical chemical neurotransmitters, have been identified in germ cells, Sertoli cells, and spermatozoa. In this study, screening of reproductive tissues revealed high levels of RESP18 protein and mRNA in the testes but not in ovaries or epididymis. The testes and sperm expressed 18-KD RESP18 and a unique 19-KD isoform. To better understand RESP18 expression in the testes, we have examined the stages of the cycle of the seminiferous epithelium by immunohistochemistry and Western blot analyses. Immunohistochemical analysis showed that RESP18 protein was expressed exclusively in spermatocytes and maturing spermatids. RESP18 protein was expressed at high levels in Step 1-8 round spermatids, in which the PC4 prohormone convertase, nerve growth factor, and proenkephalin are also expressed. Western blots, Northern blots, and indirect immunofluorescence staining demonstrated RESP18 expression in sperm.
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PMID:Stage-specific expression of RESP18 in the testes. 898 41

PACE4 is one of the neuroendocrine-specific mammalian subtilisin-related endoproteases believed to function in the secretory pathway. The biosynthesis and secretion of PACE4 have been studied using transfected neuroendocrine and fibroblast cell lines. as well as primary pituitary cultures. ProPACE4 (approx. 106 kDa) is cleaved intracellularly before secretion of PACE4 (approx. 97 kDa); the N-terminal propeptide cleavage is accelerated in a truncated form of PACE4 lacking the Cys-rich C-terminal region (PACE4s). Neither PACE4 nor PACE4s is stored in regulated neuroendocrine secretory granules, whereas pro-opiomelanocortin-derived peptides and prohormone convertase I enter the regulated secretory pathway efficiently. The relatively slow cleavage of the proregion of proPACE4 in primary anterior pituitary cells, followed by rapid secretion of PACE4, is similar to the results for proPACE4 in transfected cell lines. The enzyme activity of PACE4 is distinct from furin and prohormone convertases, both in the marked sensitivity of PACE4 to inhibition by leupeptin and the relative insensitivity of PACE4 to inhibition by Ca2+ chelators and dithiothreitol; PACE4 is not inhibited by the alpha1-antitrypsin Portland variant that is very potent at inhibiting furin. The unique biosynthetic and enzymic patterns seen for PACE4 suggest a role for this neuroendocrine-specific subtilisin-like endoprotease outside the pathway for peptide biosynthesis.
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PMID:PACE4: a subtilisin-like endoprotease with unique properties. 903 41

Using antibodies specific for pro-opiomelanocortin (POMC), amidated joining peptide (JP), and the prohormone convertase PC1, we showed immunocytochemically that PC1 in a corticotrophic tumor cell line, AtT-20, was co-localized either with POMC or with amidated JP in secretory granules, and also confirmed that POMC was cleaved mainly in secretory granules. Analysis using DAMP (3- [2,4-dinitroanilino]-3'-amino-N-methyldipropylamine) as the pH probe suggested a correlation between POMC processing and acidic pH in the secretory granules. Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase, completely inhibited POMC processing and caused constitutive secretion of the unprocessed precursor. By contrast, chloroquine, a weak base that is known to neutralize acidic organelles, was unable to inhibit POMC processing. Electron microscopic analysis revealed that, in AtT-20 cells treated with bafilomycin A1, the trans-Golgi cisternae were dilated and few secretory granules were present in the cytoplasm. These observations suggest that acidic pH provides a favorable environment for proteolytic processing of POMC by PC1 but is not required, and that integrity of the trans-Golgi network and sorting of POMC into secretory granules are important for POMC processing.
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PMID:Proteolytic processing of pro-opiomelanocortin occurs in acidifying secretory granules of AtT-20 cells. 907 24

Prohormone substrates are required for investigation of the proteolytic processing of prohormones and proproteins into active peptide hormones and neurotransmitters. However, the lack of prohormone proteins has been a limiting factor in elucidating proteolytic mechanisms for conversion of prohormones into active peptides. Therefore, in this study, cloned cDNAs encoding the prohormones proenkephalin (PE), pro-neuropeptide Y (pro-NPY), pro-opiomelanocortin (POMC), and beta-protachykinin (beta-PT) were utilized to express recombinant prohormones in Escherichia coli. High-level expression of milligrams of prohormones was achieved with the pET3c expression vector utilizing the T7 promoter for production of PE, pro-NPY, and POMC, as demonstrated by SDS-PAGE gel electrophoresis, Western blots, and 35S-methionine labeling. In addition, beta-PT was expressed at high levels as fusion proteins with the maltose-binding protein and glutathione S-transferase by the pMAL-c and pGEX-2T expression vectors, respectively. Relative rates of processing by the established processing proteases "prohormone thiol protease" (PTP), 70-kDa aspartyl protease, and PC1/ 3 and PC2 (PC, prohormone convertase) were examined with purified PE, pro-NPY, and POMC. Distinct preferences of processing enzymes for different prohormones was demonstrated. PTP preferred PE and pro-NPY substrates, whereas little processing of POMC was detected. In contrast, the 70-kDa aspartyl protease cleaved POMC more readily than pro-NPY or PE. However, PC1/3 and PC2 prefer POMC as substrate. Demonstration of selectivity of processing enzymes for prohormone substrates illustrates the importance of expressing recombinant prohormones for in vitro processing studies.
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PMID:High-level expression of the prohormones proenkephalin, pro-neuropeptide Y, proopiomelanocortin, and beta-protachykinin for in vitro prohormone processing. 917 94

Synthetic glucocorticoids have become an important clinical tool with which to advance fetal lung maturation in women at risk of early preterm birth, and this has succeeded in reducing neonatal mortality and morbidity from respiratory distress syndrome. Although previous studies have shown that glucocorticoids have deleterious consequences on fetal development, there is little information regarding the effects of clinically relevant repeated maternal doses of glucocorticoids on fetal growth and hypothalamic-pituitary-adrenal (HPA) function. We hypothesised that repeated prenatal exposure to increased concentrations of glucocorticoids would alter fetal growth and HPA axis development. Pregnant ewes were injected with betamethasone (0.5 mg/kg) or vehicle at 104, 111 and 118 days of gestation (term 150 days). Animals were sacrificed at 125 and 146 days of gestation, at which time fetal weights were recorded. Maternal and fetal blood samples were gathered and fetal tissue collected. Maternal oestradiol concentrations were significantly greater than those in controls at 125 days of gestation, but were not different at 146 days. Maternal plasma progesterone concentrations were similar between groups at both 125 and 146 days of gestation. Weight at birth was significantly reduced by 23% at 125 days and 19% at 146 days of gestation (P<0.05) after exposure to glucocorticoid. Cord plasma ACTH concentrations were not significantly different between groups at day 125, but were significantly increased in day 146 fetuses of ewes that had received betamethasone (P<0.05). Cord plasma cortisol concentrations followed the same trend, although differences were not statistically significant. Cord plasma corticosteroid binding capacity (CBC) was significantly increased at 125 days of gestation in fetuses of betamethasone-treated animals (P<0.05), but not at 146 days of gestation. To examine the mechanisms regulating the increase in cord plasma ACTH of 146-day fetuses, we used in situ hybridisation to determine the distribution and levels of mRNA encoding key pituitary and hypothalamic neuropeptides of the HPA axis. In pituitaries of 146-day fetuses, there were no significant differences in the regional pattern of distribution or amounts of pro-opiomelanocortin (POMC) mRNA between betamethasone-treated animals and controls, in either the pars intermedia or the inferior and superior regions of the pars distalis. Neither prohormone convertase (PC)-1 nor PC-2 mRNA levels in pituitaries of 146-day fetuses were significantly different between treatment groups. After maternal betamethasone, immunoreactive ACTH peptide content in the fetal pars distalis was not different but glucocorticoid receptor (GR) mRNA levels in the pars distalis were increased significantly (P<0.05). No significant difference in distribution pattern or concentrations of corticotrophin-releasing hormone (CRH) mRNA, GR mRNA, oxytocin mRNA and pre-proenkephalin mRNA were found in hypothalami from fetuses at 146 days of gestation after betamethasone treatment. We conclude that antenatal betamethasone given to pregnant sheep in a manner similar to that used in human obstetric practice results in reduced weight at birth at 125 and 146 days, and altered basal cord levels of plasma ACTH and corticosteroid binding capacity, but these changes are not reflective of changes in steady state concentrations of POMC and CRH mRNA in the fetal pituitary or hypothalamus.
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PMID:Effects of repeated maternal betamethasone administration on growth and hypothalamic-pituitary-adrenal function of the ovine fetus at term. 1075 38

Although the rapid increase in the prevalence of obesity in many countries suggests that environmental factors (mainly overeating and physical inactivity) play the most important role in the development of overweight, it is very likely that genetic factors also contribute. It appears that one major gene in combination with one or several minor genes constitute the genetic components behind excess accumulation of body fat in most obese individuals. However, monogenic obesity has been described in a few families due to changes in leptin, leptin receptor, prohormone convertase, pro-opiomelanocortin or melanocortin-4 receptor. None of the monogenic variants is of great importance for common human obesity; the latter genes are unknown so far. Results from genomic scans suggest that major obesity genes are located on chromosomes 2, 10, 11 and 20. Studies of candidate genes indicate that the minor obesity genes control important functions of adipose tissue, and that structural variance in these genes may alter adipose tissue function in a way that promotes obesity. Such genes are beta 2- and beta 3-adrenoceptors, hormone-sensitive lipase, tumour necrosis factor alpha, uncoupling protein-1, low-density lipoprotein receptor, and peroxisome proliferator activator receptor gamma-2. Some of these genes may promote obesity by gene-gene interactions (for example beta 3-adrenoceptors and uncoupling protein-1) or gene-environment interactions (for example beta 2-adrenoceptors and physical activity). Some are important for obesity only among women (for example beta 2- and beta 3-adrenoceptors, low-density lipoprotein receptor and tumour necrosis factor alpha). Few 'non-adipose' genes have so far shown a firm association to common human obesity, which could suggest that the important genes for the development of excess body fat also control adipose tissue function.
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PMID:Obesity--a genetic disease of adipose tissue? 1088 86

A spontaneous point mutation in the coding region of the carboxypeptidase E (CPE) gene results in a loss of CPE activity that correlates with the development of late onset obesity (Nagert, J. K., Fricker, L. D., Varlamov, O., Nishina, P. M., Rouille, Y., Steiner, D. F., Carroll, R. J., Paigen, B. J., and Leiter, E. H. (1995) Nat. Genet. 10, 135-142). Examination of the level of neuropeptides in these mice showed a decrease in mature bioactive peptides as a result of a decrease in both carboxypeptidase and prohormone convertase activities. A defect in CPE is not expected to affect endoproteolytic processing. In this report we have addressed the mechanism of this unexpected finding by directly examining the expression of the major precursor processing endoproteases, prohormone convertases PC1 and PC2 in Cpe(fat) mice. We found that the levels of PC1 and PC2 are differentially altered in a number of brain regions and in the pituitary. Since these enzymes have been implicated in the generation of neuroendocrine peptides (dynorphin A-17, beta-endorphin, and alpha- melanocyte-stimulating hormone) involved in the control of feeding behavior and body weight, we compared the levels of these peptides in Cpe(fat) and wild type animals. We found a marked increase in the level of dynorphin A-17, a decrease in the level of alpha-melanocyte-stimulating hormone, and an alteration in the level of C-terminally processed beta-endorphin. These results suggest that the impairment in the level of these and other peptides involved in body weight regulation is mainly due to an alteration in carboxypeptidase and prohormone convertase activities and that this may lead to the development of obesity in these animals.
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PMID:Impaired prohormone convertases in Cpe(fat)/Cpe(fat) mice. 1103 63

We hypothesized that the concurrent prepartum rise in adrenocorticotropic hormone (ACTH) and cortisol in the plasma of fetal sheep might be attributable to altered expression of pituitary endoproteases, prohormone convertase (PC)-1, and PC-2, or to changes in pituitary expression of glucocorticoid receptor (GR) that would influence negative feedback potential. We obtained pituitary tissue from fetal sheep during late pregnancy (d 100-d 145, term) and at precise times during the process of labor and used in situ hybridization to localize and quantify mRNA levels. Proopiomelanocortin (POMC) mRNA was regionally distributed (pars intermedia > inferior pars distalis > superior pars distalis) and increased within the pars distalis during late pregnancy and with labor. At term, levels of PC-1 and PC-2 mRNA were higher in the pars intermedia than pars distalis; PC-1 but not PC-2 in the pars distalis increased with gestational age, although it did not change further at labor. GR mRNA levels in the pars distalis increased between d 135 and term, then decreased during labor. We suggest that the concomitant rise in plasma ACTH and cortisol of fetal sheep during late gestation may be attributable, in part, to increased expression of PC-1 leading to increased POMC processing. Furthermore, the negative feedback effects of cortisol on pituitary POMC synthesis and/or ACTH release during active parturition may be lessened by downregulation of anterior pituitary GR.
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PMID:Effects of labor on pituitary expression of proopiomelanocortin, prohormone convertase (PC)-1, PC-2, and glucocorticoid receptor mRNA in fetal sheep. 1105 Oct 43

There is today growing evidence that the nervous and the immune systems can exchange information, mainly through small molecules, either cytokines or neuropeptides. Furthermore, it appears that some so-called neurotransmitters like neuropeptides can function as endogenous messengers of the immune system, and that they most likely participate in an important part in the regulation of the various components of the immune response. In this context, it is widely accepted that all organisms have processes that maintain their state of health. Failure of these processes, such as those involving naturally occurring antibacterial peptides, may lead to pathological events. The presence of antibacterial peptides on both proenkephalin invertebrate (Leeches) and vertebrate (Human) neuropeptide precursors such like enkelytin, peptide B, further supports the hypothesis that some of neuropeptide precursors are implicated in immune response. Indeed, their peptides, with their high antibacterial activities further associate opioid peptides with immune related activities. We surmise that immune signalling molecule may lead to enhanced proenkephalin proteolytic processing by prohormone convertase freeing both opioid peptides and antibacterial peptides during innate immune response. However, because it is necessary to modulate inflammation, invertebrates like leeches are also able to synthesize panoply of messengers that modulate inflammation e.g. endocannabinoids, opiates and pro-opiomelanocortin derived peptides such like adenocorticotrophin and melanostimulating hormone. This demonstrates that the equilibrium between the stimulation and the inhibition of the immune response has evolved sooner that it can be thought.
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PMID:Neuroimmunology of opioids from invertebrates to human. 1178 46

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