UNIPROT:P01189 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

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

Glucocorticoid-suppressible hyperaldosteronism (GSH) is an autosomal dominant form of familial hypertension. The biochemical abnormalities seen in this disorder may be remedied by administration of dexamethasone, implying that aldosterone synthesis is being abnormally regulated by corticotropin. The final three steps of aldosterone synthesis, 11 beta- and 18-hydroxylation and 18-oxidation, are mediated by a cytochrome P450 in the zona glomerulosa of the adrenal cortex termed CYP11B2. A related isozyme in the zona fasciculata, CYP11B1, is required for cortisol synthesis; this isozyme, which is normally expressed at much higher levels than CYP11B2, only has 11 beta-hydroxylase activity. These isozymes are encoded by genes on human chromosome 8q22. We have now studied four unrelated patients with GSH. We found that each patient has one chromosome that carries three CYP11B genes instead of two. This has presumably been generated by unequal meiotic crossing-over. The extra gene is a hybrid with 5' regulatory and coding regions corresponding to CYP11B1 and 3' coding regions from CYP11B2. The breakpoint is in intron 2 in two cases, intron 3 in one, and exon 4 in one. Cells transfected with hybrid cDNAs containing up to the first three exons of CYP11B1 synthesized aldosterone at levels near that of cells carrying normal CYP11B2, but cells transfected with hybrids containing the first five or more exons of CYP11B1 could not synthesize detectable amounts of aldosterone. These data demonstrate that GSH is caused by expression of a gene that is regulated like CYP11B1 but that encodes a protein able to synthesize aldosterone.
...
PMID:Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2. 151 66

In mammalian and fish species, P450c17 mediates both 17 alpha-hydroxylase and 17,20-lyase activities in the synthesis of steroid hormones. Previous results have shown that among the adrenal steroid hydroxylase enzymes involved in adrenal C19 steroid and glucocorticoid synthesis, regulation of cytochrome P450c17 is of primary importance because it is localized at the key branch between glucocorticoid and C19 steroid synthesis. A cDNA library from guinea pig adrenal was constructed, and the complete 17 alpha-hydroxylase cytochrome P450 cDNA was isolated. The guinea pig P450c17 cDNA includes the full-length coding region (1,524 nucleotide), the complete 3' untranslated region (169 nucleotide), and 39 bases of the 5' untranslated region. Our clone shares most of the features of the other P450c17 cDNAs; however, in addition, we identified a novel conserved region of 18 amino acids located in exon I between residues 80 and 97. This region presents the highest percentage of identity among the other P450c17 enzymes and is positioned one helixturn upstream of the important Ser106 on the corresponding human form. On Northern blot, the cDNA hybridizes with a major 1.8-kb mRNA and with two other related P450c17 mRNA of about 3 and 4 kb. P450c17 mRNA is equally distributed in male and female gonads and adrenals. Characterization of the enzymatic activity shows that 17 alpha-hydroxylase and 17,20-lyase are carried by a single protein, but in homogenates 17,20-lyase activity is barely detectable. Moreover, we demonstrate in vitro and in vivo that the guinea pig enzyme preferentially has very high levels of 17 alpha-hydroxylase and 17,20-lyase activities only toward delta 4 steroids. Second-messenger cyclic adenosine monophosphate and adrenocorticotropin specifically increased the abundance of P450c17 mRNA levels in guinea pig adrenal cells.
...
PMID:Molecular cloning and expression of guinea pig cytochrome P450c17 cDNA (steroid 17 alpha-hydroxylase/17,20 lyase): tissue distribution, regulation, and substrate specificity of the expressed enzyme. 781 86

Among the large number of immediate early genes, nuclear proto-oncogenes of the Fos and Jun families, have been postulated to be involved in the long-term effects of several growth factors on cell differentiation and/or multiplication. Since adrenal cell differentiated functions appear to be regulated by specific hormones and growth factors, the effects of these factors on proto-oncogene mRNA levels were analysed in bovine adrenal fasciculata cells (BAC) in culture. Corticotropin (ACTH) and insulin-like growth factor I increased c-fos and jun-B mRNA, but had no effect on c-jun mRNA and these early changes were associated with a later increase in BAC specific function [ACTH receptors, cytochrome P450 17 alpha) and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD)] and an enhanced steroidogenic responsiveness to both ACTH and angiotensin-II (A-II). On the other hand, A-II increased the three proto-oncogene (c-fos, c-jun and jun-B) mRNAs, induced a decrease of P450 17 alpha and 3 beta-HSD and caused a marked homologous and heterologous (ACTH) densitization. Transforming growth factor beta 1 which only increased jun-B mRNA, markedly reduced BAC differentiated functions and the steroidogenic responsiveness to both ACTH and A-II. Thus, it is postulated that the proto-oncoproteins encoded by the immediate early genes may play a role in the long-term effects of peptide hormones and growth factors on BAC differentiated functions.
...
PMID:Peptide hormone and growth factor regulation of nuclear proto-oncogenes and specific functions in adrenal cells. 791 7

The major cytochrome P450 (P450EF) in the mouse embryo fibroblast C3H/10T1/2CL8 (10T1/2) cell line, which is very active in polycyclic aromatic hydrocarbon metabolism, is immunologically distinct from known P450 families but shares homology with an adrenocorticotropin hormone-regulated P450 from rat adrenal glands (P450RAP). P450EF is more effectively induced by benz[a]anthracene (BA) than by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is anomalous for aryl hydrocarbon receptor (AhR)-mediated transcriptional activation. Evidence is presented here that induction of P450EF is consistent with mediation by the AhR but also involves an additional selective stabilization of P450EF by BA. P450EF-specific mRNA was measured by in vitro translation of 10T1/2 mRNA and subsequent immunoprecipitation with antibodies that recognize P450EF. P450EF mRNA was equally stimulated (> 10-fold) by BA (10 microM) and TCDD (10 nM) after 6 hr of induction in 10T1/2 cells. This equal stimulation of P450EF by BA and TCDD is consistent with transcriptional activation of the gene by the AhR. BA induction of mRNA declined 3-fold between 6 and 18 hr, due to metabolism of BA. Steady state P450EF mRNA levels declined quickly once this stimulation was removed, whereas total P450EF protein levels, measured by immunoblotting, continued to increase. During a 6-hr inhibition of protein synthesis with cycloheximide, both total P450EF and functional cytochrome, measured by polycyclic aromatic hydrocarbon metabolism, decreased by 60% in uninduced and TCDD-induced transformed 10T1/2 cells. This is consistent with relatively rapid degradation of P450EF (t1/2 = 4 hr). No such decline was seen when BA was present, indicating a stabilization of P450EF, which can explain the additional effectiveness of BA in enhancing the level of P450EF.
...
PMID:Dual regulation of cytochrome P450EF expression via the aryl hydrocarbon receptor and protein stabilization in C3H/10T1/2 cells. 802 8

In previous studies cadmium chloride (CdCl2) nonlethally inhibited Y-1 mouse adrenal tumor cell 20-dihydroxyprogesterone (20DHP) secretion, affecting unstimulated and stimulated steroidogenic pathway sites differently. In addition, dibutyryl cAMP-stimulated 20DHP secretion was unaffected by CdCl2, while the site of the unstimulated effect was indirectly shown to involve steps between endogenous cholesterol utilization and 20-hydroxycholesterol association with mitochondrial cytochrome P450 side-chain cleavage enzyme. In the present study we determined CdCl2 effects on plasma membrane sites preceding pre-dbcAMP-stimulation of 20DHP secretion. Y-1 cells were incubated 0.5 h in medium with or without cadmium (using the concentration that inhibited adrenocorticotropin- (ACTH)-stimulated steroid secretion by 50%) together with exogenously added maximally stimulating concentrations of ACTH, cholera toxin, forskolin, or adenosine triphosphate. Cholera toxin, forskolin and ATP bypass specific plasma membrane sites involved in the synthesis of intracellular cAMP and activate the steroid hormone biosynthetic pathway. Cadmium effects on ACTH-stimulated endogenous cAMP secretion were also examined. CdCl2 significantly reduced Y-1 cell 20DHP secretion following exposure to ACTH, cholera toxin, forskolin, and ATP; it also significantly decreased endogenous cAMP secretion into culture medium. These data may be interpreted to suggest that CdCl2 altered Y-1 cell regulation of adenyl cyclase activity, which reduced cAMP-activated cholesterol uptake by mitochondria as a consequence.
...
PMID:Modulation of adrenal cell functions by cadmium salts: 3. Sites affected by CdCl2 during stimulated steroid synthesis. 807 21

After postnatal day 1 (d1), the hypothalamo-pituitary-adrenal axis of neonatal rats becomes less responsive to certain stimuli for up to 2 weeks. The present study was designed to quantify the development of adrenocortical cell responsiveness to its normal secretagogue, adrenocorticotropic hormone (ACTH), and to better localize intracellular sites of adrenal cell hyporesponsivity. Maximum steroidogenic responses of collagenase-dispersed adrenocortical cells (using two isolation methods) to ACTH varied significantly in the order adult > d1 > d10. The response pattern to dibutyryl cAMP ((Bu)2cAMP) was identical to that observed for ACTH (adult > d1 > d10), suggesting that neonatal adrenal responsiveness is limited by a site distal to cAMP formation. Sensitivity (EC50) of adult cells to ACTH was approximately 3-fold greater than in neonatal cells, but there was no age-dependent shift in sensitivity to (Bu)2cAMP. 20 alpha-Hydroxycholesterol (20 alpha-OHCHOL), a membrane permeable analog of cholesterol, also failed to normalize the d10 adrenal response to ACTH. This result indicates that one site of refractoriness is apparently distal to cholesterol transport, and strongly suggests possible differential cytochrome P450 enzyme expression or activity in neonatal rat adrenal cells. Finally, although stimulated secretion was lower in neonatal cells, basal corticosterone secretion was significantly greater in neonatal adrenals, suggesting that constitutive activity of neonatal adrenal cells is high compared to that of adult cells.
...
PMID:Steroidogenesis in isolated adrenocortical cells during development in rats. 838 18

This review highlights contributions from my laboratory in which the sites and mechanisms of action of the adrenocorticotropic hormone (ACTH) in the adrenal cortex have been explored. Early studies showing that ACTH stimulates adrenal steroidogenesis by interacting with specific receptors at the cell surface are summarized. Next, the development of a strategy of genetic analysis to define the signalling events that follow ACTH interaction with its receptor is described. This strategy involved the isolation and characterization of mutant adrenal cell lines harboring specific defects in the ACTH-responsive steroidogenic pathway. I describe the isolation and characterization of several of these mutants and demonstrate how these mutants have helped to establish obligatory roles for adenylyl cyclase, cyclic AMP (cAMP), and cAMP-dependent protein kinase in the steroidogenic actions of ACTH. Finally, some of our studies on the regulated expression of the steroidogenic cytochrome P450 enzymes in Y1 adrenal cells are reviewed. These latter studies have led to the discovery of a novel promoter element and transcription factor (designated steroidogenic factor 1) that participates in the coordinate expression of these cytochrome P450 enzymes and that is required for their regulated expression by ACTH and cAMP.
...
PMID:The 1994 Upjohn Award Lecture. Molecular and genetic approaches to the study of signal transduction in the adrenal cortex. 856 76

Cimetidine is commonly used for stress ulcer prophylaxis in intensive care patients. Cimetidine contains an imidazole structure. Similar drugs have been shown to inhibit steroid synthesis by blocking cytochrome P450-dependent reactions in the adrenal cortex. It is suggested that bolus injections of cimetidine suppress the normal corticosteroid production. This might be deleterious since a decreased cortisol response seems to be associated with increased mortality during chronic severe stress. We therefore performed a prospective, randomized, and controlled study to assess the effect of a short-term continuous infusion of either cimetidine or ranitidine, a non-imidazole H2-pantagonist, upon cortisol secretion in a cohort of hemodynamically stable intensive care patients. Twenty patients were consecutively enrolled following determined inclusion criteria and divided in three treatment groups: 6 controls, 7 cimetidine- and 7 ranitidinetreated subjects. Both cimetidine (1200 mg) and ranitidine (200 mg) were administered by infusion pump over 24 hrs. A short corticotropin test was done within 24 hrs after admission (d0) and repeated 7 days thereafter (d7). On both occasions, plasma cortisol was measured immediately before the test and 30 min afterwards. The three treatment groups presented a normal cortisol response at d0 and d7. Peak cortisol levels after stimulation did not show any significant difference for both the cimetidine and the ranitidine group, either at d0 or at d7. Moreover, this response at d0 and d7 was also not significantly different from the one observed in the controls. From this study we can conclude that one week treatment with conventional intravenous doses of cimetidine does not induce significant alterations of the cortisol response in hemodynamically stable ICU patients.
...
PMID:One week treatment with cimetidine does not attenuate the cortisol response to a short corticotropin test in stable intensive care patients: a prospective, randomized, and controlled study. 866 19

The functional development of the neonatal rat adrenal cortex is characterized by a triphasic response to adrenocorticotropic hormone (ACTH), with a nadir in responsiveness around neonatal day 10 (d10). In this study, the hypothesis was tested that hyporesponsiveness to ACTH partly results from deficiencies in steroidogenic enzyme content. Immunoreactive (ir) levels of mitochondrial cytochrome P450 enzymes (side chain cleavage (P450scc) and 11 beta-hydroxylase (P450c11)) did not change during neonatal development. Immunoreactive levels of microsomal 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta-HSD), however, were significantly and comparably lower in both day 1 (d1) and d10 neonates compared to adult rats. Activity of 3 beta-HSD did not parallel changes in ir 3 beta-HSD content. Enzyme activity was low on d1 (approximately 39% of adult activity), but by d10 was statistically equivalent to that of microsomes from adult adrenal glands. Immunoreactive levels of microsomal cytochrome P450 21 alpha-hydroxylase (P450c21) were significantly lower in d1 glands than in adult glands (by approximately 50%), but by d10 were statistically indistinguishable from adults. On the other hand, P450c21 activity was equivalent on d1 and d10 and both were significantly lower compared to adults (approximately 62% of adult activity). ACTH injections from d3-d10 facilitated the adrenocortical steroidogenic response to ACTH on d10. This treatment increased levels of ir 3 beta-HSD, but not ir P450c21. The results suggest that rat adrenocortical 3 beta-HSD and P450c21 are developmentally and differentially regulated, and that ir levels of the proteins are not correlated with enzyme activity during the neonatal period. One possible explanation for these observations is that multiple isoforms of the two enzymes, with different antigenic and enzymatic properties, may be expressed during development at different times. In addition, the combined decreased activities of these two enzymes can almost entirely account for the decreased steroidogenic output of rat adrenocortical cells on d1, but not during the later neonatal period.
...
PMID:Ontogeny of immunoreactive and bioactive microsomal steroidogenic enzymes during adrenocortical development in rats. 867 48

We have previously demonstrated that corticotropin-releasing hormone (CRH) treatment of MA-10 mouse Leydig tumor cells results in a dose-dependent stimulation of progesterone production. In view of this observation we wished to determine the effects of CRH on the synthesis of the steroidogenic acute regulatory (StAR) protein in these cells. StAR is a steroidogenic tissue-specific, hormone-induced, rapidly synthesized protein previously shown to be involved in the acute regulation of steroidogenesis, probably by promoting the transfer of cholesterol to the inner mitochondrial membrane and the cytochrome P450 side-chain cleavage enzyme. Treatment of MA-10 cells with the cAMP analogue dibutyryl cAMP (dbcAMP) resulted in a dose- and time-dependent increase in the levels of StAR protein that reached a maximum at 800 microM dbcAMP and within a time period of 6 h. Further, treatment of MA-10 cells with CRH also resulted in a dose-dependent increase in the synthesis of the StAR protein with a maximal response observed at 1 microM. Slightly different from that observed with dbcAMP, the maximal response to 1 microM CRH was seen at 4 h following stimulation. These results indicate that the observed increase in steroid production in response to CRH in MA-10 Leydig tumor cells is similar to that previously seen with trophic hormone stimulation acting through the cAMP second messenger pathway, and that it occurs as a result of an increase in the synthesis of the StAR protein.
...
PMID:Corticotropin-releasing hormone stimulates the expression of the steroidogenic acute regulatory protein in MA-10 mouse cells. 928 89

1 2 3 4 5 Next >>