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

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

Steroidogenic factor-1 (SF-1) is a nuclear receptor that is essential for the proper development and function of steroid hormone-producing cells. The activation function-2 (AF-2) domain in SF-1 is a short alpha-helix in the C terminus that is conserved with respect to other nuclear receptors and is important for transactivation of target genes. In order to investigate the possible role of the AF-2 domain of SF-1 in cAMP-dependent transcriptional regulation of the bovine steroid hydroxylase gene CYP17, mutations were introduced and the effects were characterized. The mutant SF-1 proteins were expressed at comparable levels in nonsteroidogenic Cos-1 cells that lack SF-1, and their abilities to bind an SF-1 site from the CYP17 gene were not affected. Transient transfections of wild-type and mutant SF-1 in Cos-1 cells showed that the capacity to transactivate a reporter gene under the control of the SF-1 site from CYP17 was reduced by the mutations in the AF-2 domain of SF-1. A point mutation in the AF-2 region, E454A, resulted in a relative reporter gene activity that was 21% of that observed with wild-type SF-1. Co-transfections of adrenocortical Y-1 cells, which express endogenous SF-1, with the catalytic subunit of cAMP-dependent protein kinase (PKA-C) and the SF-1-dependent reporter gene showed on average a 16-fold increase in activity in the presence of PKA-C. Introduction of the AF-2 mutants of SF-1 into Y-1 cells completely abolished the PKA-C-mediated stimulation of the reporter gene. The transdominant negative effect of the mutant SF-1 proteins suggests that the AF-2 domain is essential for the activation of SF-1 by the cAMP-dependent protein kinase-dependent signaling pathway.
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PMID:Mutations in the activation function-2 core domain of steroidogenic factor-1 dominantly suppresses PKA-dependent transactivation of the bovine CYP17 gene. 959 68

cAMP-dependent transcription of steroid hydroxylase genes involves activation of cAMP-dependent protein kinase (PKA) and subsequent phosphorylation of downstream target proteins. Although the requirement for the activation of PKA is well established, none of the transcription factors required for steroid hydroxylase gene transcription have been found to be PKA phosphoproteins. In this study we examined the role of changes in phosphorylation state on the expression and transcriptional activity of the human CYP17 gene (hCYP17). Using inhibitors of serine/threonine phosphatase activity (okadaic acid) and phosphotyrosine phosphatase activity (peroxyvanadate), we can inhibit the cAMP-inducible binding of the steroidogenic factor-1 (SF-1), p54(nrb)/NonO, and polypyrimidine tract-binding protein-associated splicing factor (PSF) complex required for regulation of transcription to the promoter of hCYP17. Further, both okadaic acid and peroxyvanadate attenuate cAMP-stimulated increases in endogenous hCYP17 mRNA expression and in hCYP17 promoter-reporter construct luciferase activity. In vivo phosphorylation and immunoprecipitation of SF-1 show a cAMP-stimulated decrease in (32)P-labeled SF-1. Our findings demonstrate that activation of protein phosphatase(s) is essential for cAMP-dependent transcription of hCYP17 in H295R cells and suggest a role for PKA in phosphatase activation, which leads to dephosphorylation of SF-1 and increased gene transcription.
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PMID:Adrenocorticotropin/cyclic adenosine 3',5'-monophosphate-mediated transcription of the human CYP17 gene in the adrenal cortex is dependent on phosphatase activity. 1195 59

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