Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q02318 (steroid hydroxylase)
 243 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Cytochromes P-450sec and P-450(11) beta, adrenodoxin and adrenodoxin reductase, mitochondrial components of the adrenocortical steroid hydroxylase pathway, are synthesized as higher molecular weight precursors; cytochrome P-450C-21, a microsomal component of this pathway, is synthesized as the mature form. 2. Synthesis of the above mitochondrial components is induced by ACTH in a co-ordinated fashion. Synthesis of cytochrome P-450C-21 and NADPH-cytochrome P-450 reductase is also induced by ACTH, however, the induction of these microsomal components is not co-ordinated with that of the mitochondrial components. 3. Following treatment of cultured cells with ACTH, the pattern of glucocorticoid output changes from approximately equal amounts of cortisol and corticosterone to predominately cortisol within 24 h. This change results from a large induction of cytochrome P-450(17) alpha activity in response to ACTH. 4. Bovine adrenocortical cells in culture become refractory to continued treatment with ACTH. This refractoriness is manifested in terms of steroid output; synthesis of cytochromes P-450scc, P-450(11) beta and P-450C-21, adrenodoxin and adrenodoxin reductase; and activities of cholesterol side-chain cleavage, 11 beta-hydroxylase and 17 alpha-hydroxylase.
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PMID:ACTH-mediated induction of synthesis and activity of cytochrome P-450s and related enzymes in cultured bovine adrenocortical cells. 618 84

The turnover of newly synthesized cytochromes P-450scc and P-45011 beta, and adrenodoxin was investigated in bovine adrenocortical cells in primary monolayer cultures. Cells were pulse-radiolabeled with [35S]methionine, and specific newly synthesized enzymes were immunoisolated at various times following labeling and quantitated. Adrenocorticotropin (ACTH) treatment did not alter the average turnover rate of total cellular proteins or that of total mitochondrial proteins. The half-life of total cellular proteins of control and ACTH-treated cells was determined to be 20.5 and 23 h, respectively. The half-life of mitochondrial proteins of control and ACTH-treated cells was determined to be 42.5 and 44 h, respectively. The turnover rate of newly synthesized cytochrome P-450scc was approximately the same as total mitochondrial protein (t1/2 = 38 h), and was unchanged by ACTH treatment (t1/2 = 42 h). ACTH treatment did not greatly alter the turnover rate of adrenodoxin. The half-life of adrenodoxin from control and ACTH-treated cells was determined to be 20 and 17 h, respectively. However, ACTH treatment appeared to increase the half-life of cytochrome P-45011 beta from 16 h in control cells to 24 h in treated cells. The differential rate of turnover of mitochondrial proteins studied here supports the contention that mitochondria are subject to heterogeneous degradation. It appears that chronic treatment of bovine adrenocortical cells in culture with ACTH leads to increased steroidogenic capacity, primarily as a result of increased synthesis of steroidogenic enzymes, although, as shown for cytochrome P-45011 beta, ACTH action might also increase steroidogenic capacity by increasing the half-life of this steroid hydroxylase.
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PMID:Turnover of newly synthesized cytochromes P-450scc and P-45011 beta and adrenodoxin in bovine adrenocortical cells in monolayer culture: effect of adrenocorticotropin. 632 2

This study was designed to test the hypothesis that ACTH from the fetal pituitary is a major regulator of adrenocortical steroid hydroxylase gene expression in the ovine fetus at 0.4 (60-70 days) of gestation. Pregnant ewes at 0.4 gestation received intravenous infusions of dexamethasone (0.76 mg/h, n = 13) for 48 h. The rationale for this regime was that some of the infused dexamethasone would cross the placenta and act on the fetal pituitary to suppress ACTH release. Control animals received infusions of saline (0.38 ml/h, n = 12) for 48 h. At the end of the infusion period, the animals were killed, umbilical vessel blood taken for ACTH and cortisol analyses, and the fetal adrenal glands taken for assessment of P-450scc, P-450(17 alpha) and P-450c21 levels using the techniques of hybridization histochemistry and RNase protection assay. Dexamethasone treatment decreased maternal and fetal concentrations of ACTH to 29 +/- 10 and < 20 pg/ml, respectively and cortisol concentrations to 3.5 +/- 0.6 and 3.2 +/- 0.8 nmol/l respectively. The adrenal glands from the dexamethasone-treated fetuses exhibited significantly lower levels of mRNA for P-450scc (11% of control) and P-450(17 alpha) (2% of control). These results suggest that ACTH is a major regulator of steroid hydroxylase gene expression and subsequent cortisol biosynthesis in vivo in the ovine fetus at 0.4 gestation.
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PMID:Regulation of steroid hydroxylase gene expression in the ovine fetal adrenal gland at 0.4 gestation. 795 94

As part of its trophic action to maintain the steroidogenic capacity of adrenocortical cells, corticotropin (ACTH) increases the transcription of the cytochrome P-450 steroid hydroxylase genes, including the gene encoding steroid 21-hydroxylase (21-OHase). We previously identified several promoter elements that regulate 21-OHase gene expression in mouse Y1 adrenocortical tumor cells. One of these elements, located at nucleotide -65, closely resembles the recognition sequence of the orphan nuclear receptor NGFI-B, suggesting that NGFI-B regulates this essential steroidogenic enzyme. To explore this possibility, we first used in situ hybridization to demonstrate high levels of NGFI-B transcripts in the adrenal cortex of the adult rat. In cultured mouse Y1 adrenocortical cells, treatment with ACTH, the major regulator of 21-OHase transcription, rapidly increased NGFI-B expression. Gel mobility shift and DNase I footprinting experiments showed that recombinantly expressed NGFI-B interacts specifically with the 21-OHase -65 element and identified one complex formed by Y1 extracts and the 21-OHase -65 element that contains NGFI-B. Expression of NGFI-B significantly augmented the activity of the intact 21-OHase promoter, while mutations of the -65 element that abolish NGFI-B binding markedly diminished NGFI-B-mediated transcriptional activation. Specific mutations of NGFI-B shown previously to impair either DNA binding or transcriptional activation diminished the effect of NGFI-B coexpression on 21-OHase expression. Finally, an oligonucleotide containing the NGFI-B response element conferred ACTH response to a core promoter from the prolactin gene, showing that this element is sufficient for ACTH induction. Collectively, these results identify a cellular promoter element that is regulated by NGFI-B and implicate NGFI-B in the transcriptional induction of 21-OHase by ACTH.
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PMID:The orphan nuclear receptor NGFI-B regulates expression of the gene encoding steroid 21-hydroxylase. 838 Aug 97

The action of peptide hormones from the anterior pituitary regulates transcription of a large number of genes located in most, if not all, tissues. This action is mediated through regulation of steroid hormone production in the steroidogenic factories (adrenals, gonads). These steroid hormones are transported through the circulation to the peripheral tissues where they serve as ligands for the family of zinc-finger nuclear receptor transcription factors. The mechanisms by which peptide hormones regulate steroid hormone production include a chronic response mediated by elevated levels of cAMP resulting from the binding of peptide hormones to their cell surface receptors which enhances transcription of the genes encoding steroid hydroxylases required for steroid hormone biosynthesis. The action of ACTH in the adrenal cortex has been studied in greatest detail leading to identification of unique cAMP-response sequences (CRS) in the different bovine steroid hydroxylase genes. Most likely FSH and LH mediate steroid hydroxylase gene expression in the gonads via the same response elements. Unlike developmental/tissue-specific transcription of these genes which is regulated by a common transcription factor (SF-1), cAMP-dependent transcription of each steroid hydroxylase gene requires a different transcription factor.
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PMID:Mechanisms of ACTH(cAMP)-dependent transcription of adrenal steroid hydroxylases. 896 20

The transcription of steroid hydroxylase genes is controlled by ACTH and cAMP in the adrenal cortex. In most instances the regulation appears to rely on transcription factors traditionally not associated with cAMP-dependent gene expression. For the non-traditional factors it remains necessary to elucidate the coupling of increases in intracellular cAMP and cAMP-dependent protein kinase (PKA) activity to the function of these proteins. The bovine CYP17 gene, which encodes the steroid 17 alpha-hydroxylase, contains two discrete DNA elements within its promoter and upstream region (CRS1 and CRS2) that individually can confer cAMP responsiveness. The CRS1 element is a target for PKA signalling and for negative regulation via the protein kinase C signal transduction pathway. The homeodomain protein Pbx1 enhances CRS1-dependent transcription, but additional CRS1-binding proteins remain to be identified. Furthermore it is not known how PKA regulates the activity of Pbx1 or its possible binding partners. Closer to the promoter, the nuclear orphan receptors SF-1 and COUP-TF have overlapping binding sites in CRS2 and they bind in a mutually exclusive manner with very similar affinities; 8 and 10 nM, respectively. SF-1 stimulates whereas COUP-TF inhibits transcription from the bovine CYP17 promoter. Together, the data suggest that cAMP-dependent control of the amounts of the activator SF-1 vs. the repressor COUP-TF could influence CRS2-dependent transcription. In addition, PKA may influence the phosphorylation of SF-1, thus increasing its activity. In vitro, PKA will elicit phosphorylation of SF-1. However, although SF-1 can be immunoprecipitated from adrenocortical cells as a phosphroprotein, we have not been able to show cAMP-dependent increase in net phosphorylation in intact cells. More careful examination of individual phosphorylation sites in SF-1 may still reveal hormone- and cAMP-induced phosphorylation of SF-1.
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PMID:Transcriptional regulation of the bovine CYP17 gene by cAMP. 902 13

An essential role of ACTH is to assure that optimal steroidogenic capacity is maintained in the adrenal cortex throughout life. This is achieved by maintaining transcriptional pressure on the genes encoding the adrenocortical steroid hydroxylases via the second messenger, cAMP. Even though these genes respond coordinately to cAMP, it has been surprising to discover that each gene uses its own unique cAMP response system during this coordinate response. Thus, different cis elements and sets of transcription factors control the cAMP responsiveness of each different steroid hydroxylase gene. Although the physiological basis of this diversity in biochemical mechanisms of transcriptional regulation is not apparent, a portion of this signaling pathway is common to all of these genes. In particular, the action of cAMP-dependent protein kinase and an as yet uncharacterized cycloheximide-sensitive step are necessary for ACTH-mediated transcription of each gene. Biochemical characterization of these common steps in the ACTH-dependent signaling pathways is essential to an understanding of the maintenance of optimal steroidogenic capacity in the adrenal cortex.
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PMID:Cytochromes P450 12: diversity of ACTH (cAMP)-dependent transcription of bovine steroid hydroxylase genes. 919 22

Metyrapone, a 11-beta steroid hydroxylase inhibitor that blocks stress-induced glucocorticoid release, is extensively used to study the physiological and behavioural roles of glucocorticoids. However, there is circumstantial evidence suggesting that metyrapone could act as a pharmacological stressor. Thus, the effects of various doses of metyrapone on two well-characterized stress markers (ACTH and glucose) were studied in male rats. Metyrapone administration, while exerting a modest effect on plasma corticosterone levels, dose-dependently increased plasma ACTH and glucose levels. Using the highest doses previously tested (200 mg/kg) we further observed, as evaluated by fos-like immunoreactivity (FLI), a strong activation of a wide range of brain areas, including the parvocellular region of the hypothalamic paraventricular nucleus (PVNp), the origin of the main ACTH secretagogues. Metyrapone-induced FLI was observed in neocortical and allocortical areas, in several limbic, thalamic and hypothalamic nuclei and, to a lesser extent, in the brainstem. In a final experiment, a dose-response study of metyrapone-induced FLI was carried out focusing on selected brain areas. The study revealed that the paraventricular thalamic nucleus and central amygdala were the areas most sensitive to metyrapone as they responded even to the lowest dose of the drug. Most areas, among them the PVNp, only showed enhanced FLI with the two highest doses, i.e. when it was associated with ACTH and glucose responses. These data suggest that some of the effects of metyrapone could be due to its stressful properties rather than its ability to inhibit glucocorticoid synthesis. The exact mechanisms involved remain to be established.
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PMID:Evidence that metyrapone can act as a stressor: effect on pituitary-adrenal hormones, plasma glucose and brain c-fos induction. 1227 45

Adrenal zona fasciculata (AZF) cells express a cAMP-activated guanine nucleotide exchange protein (Epac2) that may function in ACTH-stimulated cortisol synthesis. Experiments were done to determine whether cAMP analogs that selectively activate Epacs could induce cortisol synthesis and the expression of genes coding for steroidogenic proteins in bovine AZF cells. Treatment of AZF cells with the Epac-selective cAMP analog (ESCA) 8CPT-2'-OMe-cAMP induced large (>100 fold), concentration-dependent, delayed increases in cortisol synthesis and the expression of mRNAs coding for the steroid hydroxylases CYP11a1, CYP17, CYP21, and the steroid acute regulatory protein (StAR). However, a non-hydrolyzable analog of this ESCA, Sp-8CPT-2'-OMe-cAMP, failed to stimulate cortisol production even at concentrations that activated Rap1, a downstream effector of Epac2. Accordingly, putative metabolites of 8CPT-2'-OMe-cAMP, including 8CPT-2'-OMe-5'AMP, 8CPT-2'-OMe-adenosine, and 8CPT-adenine all induced cortisol synthesis and steroid hydroxylase mRNA expression with a temporal pattern, potency, and effectiveness similar to the parent compound. At concentrations that markedly stimulated cortisol production, none of these metabolites significantly activated cAMP-dependent protein kinase (PKA). These results show that one or more metabolites of the ESCA 8CPT-2'-OMe-cAMP induce cortico-steroidogenesis by activating a panel of genes that code for steroidogenic proteins. The remarkable increases in cortisol synthesis observed in this study appear to be mediated by a novel cAMP-, Epac- and PKA-independent signaling pathway.
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PMID:Metabolites of an Epac-selective cAMP analog induce cortisol synthesis by adrenocortical cells through a cAMP-independent pathway. 1956 12

Adrenocorticotropic hormone and angiotensin II stimulate cortisol secretion from bovine adrenal zona fasciculata cells by the activation of adenylate cyclase and phospholipase C-coupled receptors. Curcumin (1- 20 muM), a compound found in the spice turmeric, inhibited cortisol secretion stimulated by ACTH, AngII, and 8CPT-cAMP. Curcumin also suppressed ACTH-stimulated increases in mRNAs coding for steroid acute regulatory protein and CYP11a1 steroid hydroxylase. In whole cell patch clamp recordings from AZF cells, curcumin at slightly higher concentrations also inhibited Ca(v)3.2 current. These results identify curcumin as an effective inhibitor of ACTH- and AngII-stimulated cortisol secretion. The inhibition of Ca(v)3.2 current by curcumin may contribute to its suppression of secretion.
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PMID:Curcumin inhibits ACTH- and angiotensin II-stimulated cortisol secretion and Ca(v)3.2 current. 1965 44


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