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

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The bovine 17 alpha-hydroxylase cytochrome P450 gene (CYP17) contains at least two cAMP-responsive sequences (CRS) within its 5'-flanking region. In this study it is demonstrated that one of the sequences, CRS1, is also a target for protein kinase C (PKC)-mediated regulation. Forskolin-induced, CRS1-dependent transcription of a heterologous minimal promoter/structural gene which had been transfected into the mouse adrenocortical tumor cell line Y1 was suppressed by activation of PKC by phorbol esters such as 12-O-tetradecanoyl phorbol-14-acetate and phorbol 12,13-didecanoate-beta (PDD beta). Use of the active and inactive forms of PDD (PDD alpha and PDD beta) as well as down-regulation of PKC by prolonged treatment of the cells with 12-O-tetradecanoyl phorbol-14-acetate demonstrated that the effect of phorbol esters on transcription conferred by CRS1 was mediated through the PKC pathway and not a consequence of general toxicity to the cells. Analysis of the different steps in the signal transduction pathway between the adenylate cyclase and the CRS1 element suggests that phrobol esters do not exert their effect by altering the forskolin-induced cAMP production, activation of PKA, or the binding of nuclear proteins to CRS1. These results establish the CRS1 element as a target not only for PKA, but also for the PKC-mediated signal transduction pathway. They further suggest that PKC interferes with the transcriptional activation competence of factors bound to CRS1 and the minimal promoter.
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PMID:A novel 3',5'-cyclic adenosine monophosphate-responsive sequence in the bovine CYP17 gene is a target of negative regulation by protein kinase C. 132 75

The product of the CYP11A gene, cholesterol side chain cleavage cytochrome P450, catalyzes the initial step of steroidogenesis. A major mechanism whereby steroid hydroxylase gene transcription is regulated in the adrenal cortex requires the pituitary peptide hormone, ACTH, which acts via cAMP. We have previously identified a transcriptional enhancer in the 5'-flanking sequence [-183 to -83 base pairs (bp)] of the bovine CYP11A gene, which activates transcription of a beta-globin promoter/reporter gene in transiently transfected mouse Y1 adrenocortical tumor cells in response to the activator of adenylate cyclase, forskolin. Further deletion analysis has located the minimal cAMP-responsive sequence (CRS) to -118 to -100 bp. Analysis of DNA-protein interactions using nuclear extracts from Y1 cells revealed two protein binding sites, which were shown by competition analysis to be closely related to the two protein binding sites identified previously in the CRS of the human CYP21 gene. Namely, within the cAMP responsive fragment -118 to -100 bp, a sequence with a high degree of similarity to the consensus binding sequence for the ubiquitous transcription factor Sp1 is present, and binding of protein to this site was abolished by competition with excess GC box oligonucleotide. The second partially overlapping site is located 3' of the putative Sp1-binding site and binds to a protein identical or closely related to a putative adrenal-specific protein. Whereas the adrenal-specific protein binding site of the CYP21 CRS was previously shown to be sufficient to confer cAMP-responsive activation of transcription, the homologous site within the CYP11A CRS appears to have an attenuating effect on transcription.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:3',5'-cyclic adenosine monophosphate-dependent transcription of the CYP11A (cholesterol side chain cleavage cytochrome P450) gene involves a DNA response element containing a putative binding site for transcription factor Sp1. 133 53

In the present investigation we sought to define the specific sites in the pathway of placental progesterone biosynthesis that underlie the action of human chorionic gonadotropin (hCG). When the cells were challenged with dibutryl cAMP (dbcAMP), forskolin or isobutylmethylxanthine, they produced significantly higher amounts of progesterone which in the presence of the hCG antibody was reduced to the level of the control set of cells. Trophoblast cells cultured in serum free medium with 25-hydroxycholesterol (25-OHC) produced increased amounts of progesterone. In the presence of hCG antibody at a concentration which neutralized the secreted hCG, the steroid production was completely blocked, even when the 25-OHC was added to the medium. Also, direct quantitation of the cytochrome P450 SCC enzyme in the absence of hCG indicated a significant decrease. The exogenous addition of low density lipoproteins (LDL) increased the progesterone secretion by the trophoblast cells in culture. Neutralization of hCG by the antibodies, however, drastically reduced the LDL induced progesterone secretion, which was restored by the addition of dbcAMP to the medium. Based on these findings, we suggest a stimulatory effect of hCG on normal trophoblast cells at the level of LDL utilization and cytochrome P450 SCC enzyme. Since dbcAMP could mimic these actions of hCG, the data suggest a possible autocrine/paracrine role of hCG on the trophoblast cells. An additive effect of hCG and cAMP on progesterone secretion observed in our studies, indicate that apart from hCG, adenylate cyclase activity may also be regulated by other factors.
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PMID:Regulation of progesterone secretion in human syncytiotrophoblast in culture by human chorionic gonadotropin. 137 14

The author reviews the problem of the pattern of lipid peroxidation in cancer cells with special reference to a comparison between normal liver cells and hepatomas both transplanted and induced by diethylnitrosamine. It is stated that the loss of lipid peroxidation is proportional to the degree of de-differentiation of hepatoma cells. During carcinogenesis, however, the loss is already evident at the stage of preneoplastic nodules. A common feature of all tumors, independently of the extent of the loss of peroxidation in basal conditions, is the lack of further stimulation by ADP/iron or by ascorbate/iron. As regards the reasons for the decline in lipid peroxidation, they are certainly not unique. An important cause is the low activity of the enzymes of the monooxygenase microsomal chain. Another very important one is the change in lipid composition of membranes, with a marked decrease in polyunsaturated fatty acids, which are the main substrate for lipid peroxidation. It has been shown that enrichment of membranes of hepatomas with arachidonic acid results in restoration of stimulation of peroxidation by ascorbate/iron, but not with ADP/iron. The last type of stimulation mostly reflects the behaviour of the monooxygenase chain, whereas ascorbate/iron-induced stimulation does not require the presence of an efficient cytochrome P450-chain. Another cause for decreased lipid peroxidation in tumors is the increased rigidity of membranes, due to the large increase in cholesterol content: this prevents to some extent the influx of oxygen inside the membranes. Yet another cause is the presence of increased amounts of antioxidants in both cytosol and membranes. The main toxic product of lipid peroxidation, 4-hydroxynonenal, has been found to elicit several actions at extremely low concentrations. In fact, 4-hydroxynonenal stimulates chemotaxis of polymorphonuclear leukocytes, stimulates plasma membrane adenylate cyclase, stimulates plasma membrane guanylate cyclase, and stimulates phospholipase C. The last three enzymes involve the action of G-proteins. The effect of the aldehyde is present at less than micromolar concentrations, which may occur inside the cells in certain conditions. Moreover, at concentrations from 10(-6) to 10(-7) M, the aldehyde is able to block oncogene c-myc expression in the human erythroleukemic K562 cell line, which at the same time becomes able to express the gamma-globin gene. These facts are discussed with reference to a possible biological meaning of the loss of lipid peroxidation in tumors.
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PMID:Lipid peroxidation and cancer: a critical reconsideration. 251 Mar 83

We have investigated VIP-induced relaxation and cyclic AMP accumulation in rat thoracic aorta strips, and the importance of endothelium to both actions. The relaxation was greatly attenuated by removal of endothelium, but was unaltered by cyclo-oxygenase or lipoxygenase inhibitors. Similarly, cyclic AMP formation was nearly abolished with loss of endothelium, but was largely unaffected by inhibitors of arachidonate pathways, cytochrome P450 or guanylate cyclase. VIP may stimulate the release of a diffusible factor from endothelium (an EDRF), which activates adenylate cyclase and relaxes aortic smooth muscle.
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PMID:Vasoactive intestinal peptide evokes endothelium-dependent relaxation and cyclic AMP accumulation in rat aorta. 285 61

The CDC25 Start gene whose product appears to be required for traversing the Go phase of the cell cycle in Saccharomyces cerevisiae, has been previously cloned (J. Daniel and G. Simchen (1986), Curr Genet 10:643-646). By nucleotide sequencing of an active subclone, we found that only a region of the gene that codes for the C-terminal portion of the CDC25 protein was required for full suppression of the cdc25 mutation. The codon usage in this region indicates a poor translation of the transcript compared to genes encoding abundant proteins. The derived CDC25 protein fragment contains two regions of homology, one with the rhodopsin family, the other with the cytochrome P450 family. Strikingly, these two regions of homology are adjacent on the CDC25 protein. In view of the likely involvement of the CDC25 protein in the regulation of adenylate cyclase activity, a working hypothesis is proposed that accounts for the observed homologies.
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PMID:The CDC25 "Start" gene of Saccharomyces cerevisiae: sequencing of the active C-terminal fragment and regional homologies with rhodopsin and cytochrome P450. 332 37

Adrenal cortical mitochondria contain a mixed function oxidase capable of converting cholesterol to pregnenolone; this enzyme requires NADPH, oxygen and cholesterol. This cholesterol side chain cleavage enzyme system contains a Flavoprotein, an iron sulphur protein and a specific cytochrome P450 termed cytochrome P450scc. ACTH stimulates the adrenal cortex by activating adenyl cyclase producing an elevated intracellular concentration of cAMP. This in turn increases the activity of a cytosolic cAMP dependent protein kinase. Adrenal cortical cytosol contains a cholesterol ester hydrolase which is activated by ATP and a protein kinase. This enzyme may be deactivated by a phosphoprotein phosphatase. The adrenal cortex contains lipid droplets that are rich in esterified cholesterol. Cholesterol ester hydrolase can release free cholesterol from the lipid droplets. The free cholesterol released may be used to supplement the mitochondrial cholesterol as a pregnenolone precursor. Steroid hormone production by the adrenal cortex exhibits a diurnal rhythm and correlates with the activity of the cytosolic cholesterol ester hydrolase. The acute steroidogenic response to ACTH may be in part attributed to the availability of free cholesterol to the mitochondrial cholesterol side chain cleavage enzyme complex. The intracellular movement of free cholesterol from lipid droplets to mitochondrial inner membranes may be impeded by protein synthesis inhibitors such as cycloheximide. The precise mechanism of this block in steroidogenesis remains to be elucidated. Various drugs and oestrogenic hormones suppress the plasma and adrenal cholesterol concentrations. If adrenal cells are deficient in cholesterol, these cells exhibit a diminished response to ACTH. The response to this hormone can be corrected by supplying cholesterol via exogenous plasma lipoproteins. The route that free cholesterol follows within the adrenal cortical cell and the physiological factors influencing free cholesterol movement in such cells are important issues to be explored in future.
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PMID:Cholesterol metabolism in the adrenal cortex. 631 Feb 52

The nature of the luteolysin in humans is unknown. Hydrogen peroxide (H2O2), notably released by activated leukocytes, is generated in the rat corpus luteum at luteolysis and evokes luteolytic-like effects in rat luteal cells. We, therefore, evaluated the actions of H2O2 in human luteinized granulosa cells. After 2 days of preculture with low levels of hCG, human granulosa luteal cells were placed in suspension culture for 1 h in the presence of isobutylmethylxanthine (100 microM). A 60-min challenge with hCG evoked dose-dependent stimulation of cAMP and progesterone production. H2O2 dose-dependently inhibited progesterone production (ED50, 50-100 microM) in the absence or presence of hCG and blocked hCG-stimulated cAMP accumulation. Inhibition of progesterone synthesis by H2O2 was near maximal within 5 min, whereas inhibition of cAMP accumulation was not evident until 60 min. Cell viability was unaffected by H2O2, and inhibition of cAMP was reversible, but inhibition of steroidogenesis was long-lasting. Progesterone production stimulated by 8-bromo-cAMP, 22-hydroxycholesterol, and pregnenolone was inhibited by H2O2 as was androstenedione-dependent estradiol production. These findings indicate that H2O2 blocked progesterone synthesis by inhibition of cholesterol side-chain cleavage cytochrome P450, 3 beta-hydroxysteroid dehydrogenase, aromatase, and/or 17 beta-hydroxysteroid dehydrogenase. While H2O2 blocked stimulation of cAMP accumulation in response to hCG and cholera toxin, this same response produced by forskolin or aluminum fluoride was unaffected by H2O2. Thus, H2O2 appears to uncouple LH (hCG) receptors by interruption of G-protein-dependent activation of adenylate cyclase. In summary, H2O2 evokes effects in isolated human granulosa luteal cells that are associated with luteal regression, which raises the interesting possibility that H2O2 may serve a role as a mediator of this process like that in the rat.
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PMID:Hydrogen peroxide evokes antisteroidogenic and antigonadotropic actions in human granulosa luteal cells. 767 98

We have developed and characterized a primary cell culture system to study the regulation of 17 alpha-hydroxylase cytochrome P450 (P45017 alpha) gene expression in bovine thecal cells. Conditions have been established for the dispersal and growth of thecal cells isolated from bovine follicles, which maintain the expression of P45017 alpha for up to 8 days. Bovine theca interna cells were grown to subconfluence and transferred into medium containing forskolin, a stimulator of adenylate cyclase. Levels of P45017 alpha transcripts reached a maximum value after 48 h of stimulation with forskolin. Added progesterone was converted to 17 alpha-hydroxyprogesterone at a rate of 214 pmol/mg protein.h in cells treated with forskolin for 72 h, whereas in control cells, the rate was 9.2 pmol/mg protein.h after 72 h. This was reflected in a 10-fold increase in endogenous androstenedione production by forskolin-stimulated cells. Studies employing various growth factors suggest that transforming growth factor-beta, but not basic fibroblast growth factor, is a potent inhibitor of forskolin-induced 17 alpha-hydroxylase activity and androstenedione production in these cells. We have also characterized this cell culture system with respect to expression of other steroidogenic enzymes. Cholesterol side-chain cleavage cytochrome P450 and 3 beta-hydroxysteroid dehydrogenase transcripts as well as endogenous progesterone accumulation were increased in response to forskolin stimulation. On the other hand, aromatase cytochrome P450 expression was undetectable. The ability to maintain bovine thecal cells, which retain 17 alpha-hydroxylase activity, in culture will provide a model system to study the regulation of expression of the P45017 alpha gene in the bovine ovary.
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PMID:Maintenance and regulation of 17 alpha-hydroxylase expression by bovine thecal cells in primary culture. 767 80

The effects of elevated intracellular cyclic adenosine monophosphate (cAMP) in regulating phenobarbital (PB)-inducible gene expression in primary rat hepatocyte cultures were investigated. Cells were exposed to various concentrations (0.1-100 microM) of cAMP analogs and/or activators of intracellular cAMP-dependent pathways. Effects of these treatments were assessed either using a 1-h pulse prior to PB (100 microM) exposure or in conjunction with PB during a 24-h exposure period. PB-inducible responses were measured in hepatocytes by hybridization to cytochrome P450 (CYP) CYP2B1, CYP2B2, and CYP3A1 mRNAs. The cAMP analogs, 8-bromo-cAMP, 8-(4-chlorophenylthio)-cAMP, dibutyryl cAMP, and (Sp)-5,6-DCl-cBiMPS ((Sp)-5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole-3', 5'-monophosphorothioate), and the activators of adenylate cyclase, forskolin and glucagon, dramatically inhibited PB-mediated induction of CYP2B1 and CYP2B2 in a concentration-dependent manner. A similar inhibition of PB-induced CYP3A1 mRNA levels was effected by the cAMP analogs and glucagon. The phosphodiesterase inhibitors isobutylmethylxanthine and RO 201724 potentiated the cAMP responses. Increasing the concentration of PB (0.05-1.00 mM) did not alleviate the cAMP-mediated repression. A requirement for protein kinase A (PKA) was demonstrated by the use of (Sp)-cAMPS, a highly specific activator of PKA, whereas the inactive diastereoisomer, (Rp)-cAMPS, was ineffective in modulating PB induction. The response to cAMP was specific since elevated intracellular cAMP levels did not perturb beta-naphtholflavone-mediated induction of CYP1A1, CYP1A2, microsomal epoxide hydrolase, or dexamethasone-mediated induction of CYP3A1 gene expression. Nor did elevated intracellular cAMP modulate the liver-selective albumin gene expression levels. The results of the present study demonstrated striking inhibition of PB-mediated CYP gene induction by cAMP and PKA activators, indicating a negative regulatory role for the cAMP signal transduction pathway on PB gene induction.
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PMID:cAMP-associated inhibition of phenobarbital-inducible cytochrome P450 gene expression in primary rat hepatocyte cultures. 775 30


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