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)

Anterior pituitary POMC transcription and peptide release are negatively regulated by glucocorticoids and stimulated by CRF. Although pretreatment of corticotrope cells with CRF markedly inhibits subsequent glucocorticoid effects, the mechanism of this action is unclear. We have thus used a mouse corticotrope tumor (AtT20) cell line, to examine the effects of CRF on glucocorticoid receptor (GR) messenger RNA levels and on GR capacity/nuclear translocation. GR mRNA levels were measured by solution hybridization/S1 nuclease protection, and both total cell binding and nuclear binding were determined with [3H]dexamethasone ([3H]DEX). CRF treatment of AtT20 cells led to a rapid time-dependent decrease in GR mRNA levels which preceded a dose- and time-dependent decrease in GR binding capacity. Scatchard analysis showed a single class of high affinity binding sites (GR) in both control and CRF-treated cultures, and a decrease in the total number of GR after CRF treatment. The relative proportion of nuclear vs. cytoplasmic localized [3H]DEX-bound GR did not differ between control and CRF-treated cultures, indicating that CRF does not interfere with GR nuclear translocation. To investigate whether CRF regulates GR expression through the adenylate cyclase system, as it does POMC, AtT20 cells were treated with either forskolin or 8-bromo-cAMP, and specific nuclear GR binding was determined. Both drugs mimic the CRF-induced decrease in GR binding, and in addition forskolin decreased GR mRNA levels; in contrast, forskolin had no effect on GH3 cell GR levels. These results suggest that CRF can decrease the cellular concentration of GR, and thus potentially the response to glucocorticoids, through the same mechanism by which it stimulates anterior pituitary POMC expression.
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PMID:Adrenocorticotropin-releasing factor down-regulates glucocorticoid receptor expression in mouse corticotrope tumor cells via an adenylate cyclase-dependent mechanism. 185 64

The gene encoding proopiomelanocortin(POMC) offers an interesting model for negative regulation of gene transcription by glucocorticoids. A fragment of human genomic DNA containing the entire POMC gene, together with the neo marker gene, was introduced by transfection into the ACTH-producing mouse pituitary tumor cell line, AtT-20, and the mouse fibroblast L cell line. In the transformed AtT-20 cells the human POMC gene was transcribed correctly and the transcript was spliced faithfully. Furthermore, the addition of dexamethasone to the transformed AtT-20 cells resulted in a 40% reduction of the human POMC mRNA levels. Deletion analysis demonstrated that no more than 417 bp in the 5'-flanking region of the human POMC gene are required for transcriptional repression by glucocorticoid. This region was also responsible for the transcription induction of the human POMC gene by cyclic AMP (cAMP). In the transformed L cells, however, most of the transcripts of the human POMC gene were not correctly initiated. The addition of dexamethasone to the transformed L cells did not significantly affect the content of human POMC mRNA, although these cells expressed glucocorticoid receptor(GR). However, the increase of the transcripts by forskolin, a post-receptor adenylate cyclase-activating agent, was partially but significantly suppressed by dexamethasone in the transformed L cells. These results suggest that binding of GR to the negative glucocorticoid response element (nGRE) could lead to steric occlusion of positive transcription factors, such as cAMP-response element binding protein and tissue specific factors or that GR bound to nGRE could interact with DNA-bound positive factors in such a way as to prevent their transcriptional stimulatory activity.
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PMID:Molecular mechanisms of glucocorticoid inhibition of human proopiomelanocortin gene transcription. 195 35

The regulation by dexamethasone of beta 1- and beta 2-adrenergic receptor expression during the adipose differentiation of 3T3-F442A cells was investigated at the receptor protein and mRNA level. Preadipocytes were poorly responsive to beta-adrenergic receptor (beta-AR) agonists and expressed few beta-ARs (approximately 3,000 sites/cell) solely of beta 1 subtype. Differentiation increased adrenergic sensitivity and total beta-AR number (approximately 16,000 sites/cell) with a beta 1/beta 2 ratio of approximately 90/10. Long term exposure of either differentiating cells or mature adipocytes to dexamethasone induced down-regulation of (-)-isoproterenol-sensitive adenylate cyclase activity which paralleled a 2- to 3.5-fold decrease in beta-ARs, while the beta 1/beta 2 ratio switched to approximately 20/80. The ratios of beta 1/beta 2 binding sites were always consistent with the rank order of potency of beta-adrenergic agonists in stimulating the adenylate cyclase system. The action of steroid agonists and antagonist suggested a glucocorticoid receptor-mediated mechanism. The beta 1-AR mRNA (3.2 kilobases) was stimulated 3-4.7 times in differentiated cells, as compared with preadipose cells; this beta 1-AR transcript was repressed in dexamethasone-treated cells. The beta 2-AR mRNA species (2.3 kilobases), absent in preadipocytes, was expressed at low levels in untreated adipocytes, but reached 11-fold this level in dexamethasone-exposed cells. The switch in receptor subtype protein and mRNA levels elicited by dexamethasone demonstrates the differential genetic control by glucocorticoids of beta-AR subtype expression in 3T3-F442A cells. We suggest that this regulation of beta-AR gene expression requires interactions of glucocorticoid receptors with specific DNA targets and with one (or several) transcription factor(s) that are cell- and differentiation state-dependent.
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PMID:Differential regulation of beta 1- and beta 2-adrenergic receptor protein and mRNA levels by glucocorticoids during 3T3-F442A adipose differentiation. 197 11

Central catecholamine (CA)-neuropeptide Y (NPY) interactions and their regulation by glucocorticoids have been analyzed in vivo and in vitro, especially in the dorsal cardiovascular center of the medulla oblongata, including the nucleus tractus solitarius (nTS), using immunocytochemical, receptor autoradiographical, biochemical, and physiological techniques. Intraventricular (i.v.t.) injections of NPY in a low (7.5 pmol) or a high (1.25 nmol) dose increased adrenaline levels 4 h later in the caudal part of the dorsomedial medulla. Furthermore, NPY immunoreactivity (IR) tended to decrease in the rostral part of the dorsomedial medulla 5 min after injection of clonidine (1 microgram) in the alpha-chloralose anaesthetized rat. Thus, presynaptic interaction between NPY and adrenaline (A) mechanisms may exist in the dorsal cardiovascular center taking place at the network local circuit level or the membrane level of the NPY/A costoring synapses of the dorsomedial medulla. In vitro NPY (10 nM) reduced the affinity of the alpha 2-adrenergic agonist binding sites in the nTS, and clonidine (10 nM) reduced the 125I-NPY binding in the dorsomedial medulla. These results indicate the existence of postsynaptic receptor-receptor interactions between alpha 2-adrenergic and NPY receptors in the dorsal cardiovascular center. This interaction may in part take place at the level of the Ni protein, since NPY (300 nM) inhibited cyclic AMP (cAMP) accumulation in slices of the dorsomedial medulla. However, the interactions also probably take place at the proteins carrying the recognition sites, since NPY and adrenaline together given i.v.t. significantly antagonized the hypotensive effects of one another. Thus, the reduced affinity of the alpha 2-adrenergic receptor induced by NPY may reflect a reduced efficiency of this receptor and not an increased coupling of Ni protein to the adenylate cyclase. Thus, the postsynaptic interaction between the two receptors represents inter alia a sensitivity regulation of the two receptors. Evidence is also presented for the existence of a glucocorticoid regulation of NPY IR neurons, especially of those innervating the locus coeruleus, since after 2 weeks adrenalectomy reduced NPY IR in this area. Furthermore, glucocorticoid receptor IR was demonstrated in the nuclei of NPY nerve cell bodies of the nTS. Thus, glucocorticoids exert direct actions on cardiovascular NPY/CA costoring neurons, actions that may contribute to their hypertensive effects in humans.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Central catecholamine-neuropeptide Y interactions at the pre- and postsynaptic level in cardiovascular centers. 245 56

Exposure of adipose tissue fragments to dexamethasone leads to enhanced lipolytic and cyclic AMP responses of isolated fat cells to isoproterenol. This permissive effect of the steroid is dose-dependent, prevented by the glucocorticoid receptor antagonist RU 38486, maximum after 48 h exposure to 10 nM dexamethasone and affects only the amplitude of the maximal response (+50%). Exposure to dexamethasone also induces an increase in both the number of beta-adrenergic receptors (+30%), and the adenylate cyclase-catalytic activity (+64%) and - responses to GTP (+114%) and isoproterenol (+55%). These data strongly suggest that the permissive effect of glucocorticoids towards lipolysis "in vivo" results at least in part from a glucocorticoid-receptor mediated action of these hormones on the fat cell membranous components involved in the beta-adrenergic control of lipolysis.
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PMID:Permissive action of glucocorticoids on catecholamine-induced lipolysis: direct "in vitro" effects on the fat cell beta-adrenoreceptor-coupled-adenylate cyclase system. 283 19

Effects of glucocorticoids on the epidermal beta-adrenergic adenylate cyclase system were investigated. Long-term incubation of pig skin slices in RPMI 1640 medium resulted in the gradual decrease in the epinephrine-induced cyclic AMP accumulations of skin. The addition of hydrocortisone (100 microM) in the incubation medium prevented this decrease, and after 24- and 48-h incubation, there was a marked difference in beta-adrenergic responsiveness between control and hydrocortisone-treated skin. The study using other steroid hormones revealed that this effect on the beta-adrenergic system was relatively specific for glucocorticoids. Hydrocortisone, prednisolone, dexamethasone, and beta-methasone-17-valerate were shown to have marked effects on the beta-adrenergic system, while androstenedione, testosterone, dihydrotestosterone, progesterone, estrone, and beta-estradiol had no effect. Cortisone and estriol were shown to have similar but weaker effects than hydrocortisone. The effect of glucocorticoids was also relatively specific to the beta-adrenergic system, since there was no significant difference in adenosine-or histamine-induced cyclic AMP accumulations of skin after long-term incubation with and without hydrocortisone. The mechanism of this glucocorticoid action does not seem to be through the simple protection of the beta-adrenergic system of the skin, since the addition of hydrocortisone in the incubation medium at 24 or 48 h incubation time, when the epinephrine-induced cyclic AMP accumulation was considerably decreased, reversed the epinephrine unresponsiveness of the skin, after the additional 24-h incubation. Furthermore, the effect of hydrocortisone was inhibited by 3 different kinds of inhibitors: (a) progesterone, an inhibitor of intracytoplasmic glucocorticoid receptor binding; (b) actinomycin D, an inhibitor of messenger RNA (mRNA) synthesis; and (c) cycloheximide, an inhibitor of protein synthesis at the translation step. These results are in accordance with the view that glucocorticoids affect the beta-adrenergic system of epidermis by a mechanism requiring mRNA and protein synthesis possibly through the intracytoplasmic glucocorticoid receptor system of epidermis.
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PMID:Effects of glucocorticoids on the beta-adrenergic adenylate cyclase system of pig skin. 630

In the present study, the effects of glucocorticoids and forskolin, an activator of adenylate cyclase, were examined on neurotensin (NT) production from rat hypothalamic neurons in primary culture. Treatment with dexamethasone induced a dose-dependent increase in NT content. The maximum was reached at 1 microM dexamethasone, which induced a 100% increase in NT levels. The effect of dexamethasone was mimicked by the glucocorticoid agonist RU28362 and blocked by the antiglucocorticoid RU38486, suggesting that this effect was mediated through the glucocorticoid receptor. The treatment with dexamethasone also enhanced the number of immunoreactive NTergic cells (92% increase). In contrast to dexamethasone, forskolin affected neither the NT content nor the number of immunoreactive NTergic cells. However, when cells were treated with both dexamethasone and forskolin, a 285% increase in NT content and a 430% increase in the number of immunoreactive NTergic cells were observed, representing 2.8- and 4.7-fold increases, respectively, compared to the effect of dexamethasone alone. Moreover, this combined treatment increased the accumulation of NT in the culture medium (160% increase) as well as the abundance of NT messenger RNA. We conclude from the present findings that dexamethasone and forskolin act synergistically to enhance NT production in hypothalamic neurons.
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PMID:Effects of dexamethasone and forskolin on neurotensin production in rat hypothalamic cultures. 775 Apr 77

The biological effects of pituitary adenylate cyclase-activating peptide (PACAP) 27 and 38 on peptide secretion and gene regulation were studied in the mouse corticotrope-derived cell line AtT20. Treatment of these cells with PACAP 27/38 led to a dose-dependent increase in cAMP content and ACTH accumulation in the medium with an apparent ED50 value close to 10(-9) M. The genomic effects of PACAP were first investigated by using a reporter gene containing a cAMP responsive element (CRE: TGACGTCA) PACAP 27/38 stimulate transcription from this construction and the effect is further increased when cells are cotreated with the phosphodiesterase inhibitor rolipram. Furthermore, we show by measuring nuclear heterologous proopiomelanocortin (POMC) RNA levels or by using a reporter gene containing the POMC promoter region, that PACAP stimulates POMC transcription. This transcriptional stimulation is mediated by the cAMP-dependent protein kinase (PKA) since genetic inactivation of PKA by a dominant inhibitory mutant of this enzyme completely abolished the effect of PACAP on POMC transcription. Finally, we show that the transcriptional stimulation of POMC by PACAP is repressed by the glucocorticoid receptor agonist dexamethasone. Taken together, these data suggest that PACAP is a hypophysiotropic hormone that exert similar if not identical functions as corticotropin-releasing hormone (CRH) on corticotrope cells.
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PMID:Pituitary adenyl cyclase-activating peptide: a hypophysiotropic factor that stimulates proopiomelanocortin gene transcription, and proopiomelanocortin-derived peptide secretion in corticotropic cells. 784 39

The modulation of dopamine DA1 receptors of cultured rat renal arterial smooth muscle cells by glucocorticoid and sodium chloride was studied. At a concentration of 10 nM, the synthetic glucocorticoid dexamethasone increased maximum receptor binding but had no effect on the dissociation constant. However, the maximum binding of [3H]Sch-23390 in cells treated with 100 mM sodium chloride did not change. However, the dissociation constant for DA1 receptor was increased by adding sodium chloride. The glucocorticoid effect on DA1 of arterial smooth muscle cells became apparent after hours of incubation in the presence of the steroid and was significantly inhibited by cycloheximide (10 micrograms/ml) or by the glucocorticoid receptor antagonist RU-38486, indicating that the effect required protein synthesis through glucocorticoid receptors. Treatment of cells with 1 microM dexamethasone for 24 h increased basal and DA1-stimulated adenylate cyclase activity. Basal adenylate cyclase was decreased by sodium chloride in a dose-dependent manner. These results suggest differential control of DA1 receptors on vascular smooth muscle cells by glucocorticoid or sodium chloride.
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PMID:Dopamine DA1 receptors on vascular smooth muscle cells are regulated by glucocorticoid and sodium chloride. 809 5

The effect of dexamethasone on ACTH-induced accumulation of CYP11A and CYP17 mRNAs was studied in bovine adrenocortical cells in primary culture. The cells were treated with either ACTH (1 microM) or the adenylate cyclase activator forskolin (25 microM) and/or dexamethasone (100 nM). The accumulation of CYP11A and CYP17 mRNAs was evaluated by Northern blot analysis with the use of [alpha-32P]deoxy-CTP-labeled bovine CYP11A and CYP17 cDNAs. Chloramphenicol acetyltransferase (CAT) activity was monitored in bovine adrenocortical cells transfected with recombinant plasmids containing either CYP11A or CYP17 regulatory regions coupled to the CAT reporter gene and treated with forskolin and/or dexamethasone. Dexamethasone treatment of the cells cultured in the presence of ACTH or forskolin resulted in about 50% suppression of both CYP11A and CYP17 mRNA accumulation, with a concomitant fall in cortisol secretion to about 60% of the stimulated value. The effects of dexamethasone on accumulation of CYP11A and CYP17 mRNAs and cortisol secretion were blocked by pretreatment of the cells with RU 486 (100 nM), while RU 486 had no effect on forskolin-induced accumulation of either mRNA or cortisol secretion. Dexamethasone also inhibited the forskolin-induced expression of the transfected CYP11A- or CYP17-CAT constructs in bovine adrenocortical cells. The inhibitory effect of dexamethasone was greatly reduced by cotreatment of the transfected cells with RU 486. It is concluded that dexamethasone inhibits the ACTH-induced accumulation of CYP11A and CYP17 mRNAs at a transcriptional level and that the effect of dexamethasone is mediated by the glucocorticoid receptor.
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PMID:Dexamethasone inhibits corticotropin-induced accumulation of CYP11A and CYP17 messenger RNAs in bovine adrenocortical cells. 838 39


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