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)

Isoproterenol, corticotropin (ACTH), and triodothyronine immobilized on glass and Sepharose beads by diazotization procedures have been shown to interact with cultured tumor cells of "target tissue" origin. Cells used were rat glioma cells (C6), rat adrenal tumor cells (Y-1), and rat pituitary tumor cells (GH3). The rat glioma cells bound principally to immobilized isoproterenol, whereas the rat adrenal tumor cells bound to immobilized corticotropin, and rat pituitary tumor cells bound to immobilized triiodothyronine. Binding was inhibited by preincubation of the cells in soluble drug or hormone. With C6 cells there was a positive correlation between adenylate cyclase [ATP pyrophosphate-lyase (cyclizing, EC 4.6.1.1] stimulation and the degree of binding to the immobilized isoproterenol. Norepinephrine, bound through the ethanolamine side chain via an amide linkage, did not bind cells, demonstrating specific structural requirements for drug-cell interactions. HeLa cells were shown to bind tightly to diphtheria toxin coupled to Sepharose beads via an amide bond. This binding was inhibited by prior incubation of the Sepharose toxin with purified antitoxin. Toxin bound to Sepharose via an azo bond did not bind cells. These data suggest that the cell affinities are due to cell surface receptors interacting with the immobilized drugs and hormones, and that the observed affinities possibly reflect the relative receptor complement of these cells.
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PMID:Affinity isolation of cultured tumor cells by means of drugs and hormones covalently bound to glass and Sepharose beads. 18 May 34

Fluoride-stimulated adenylate cyclase is demonstrated inisolated tumor cells of transplantable rat pituitary tumor MtT-F4 in vitro. The intracellular cyclic adenosine 3':5'-monophosphate is lowered in the cells incubated in the presence of synthetic somatostatin. Contrary to the findings reported for normal pituitary, however, the immunoreactive growth hormone release does not change when either somatostatin or phosphodiesterase inhibitors are present in the incubation medium. The presence of dibutyryl cyclic adenosine 3':5'-monophosphate (5 mM) in the incubation medium does not change the rate of growth hormone release by isolated tumor cells.
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PMID:Effect of somatostatin on growth hormone release by MtT-F4 rat pituitary tumor in vitro. 19 84

The somatostatin (SS) analog octreotide has been successfully used in the treatment of (neuro)endocrine tumors. The mechanism of action of the tumor (growth) inhibitory action by octreotide is not fully understood. We have investigated the effect of octreotide on 7315b rat pituitary tumor cell growth, PRL release, and intracellular PRL concentrations in vitro. When cultured in medium with 10% fetal calf serum, the number of high affinity SS receptors increased with increasing culture time. On days 7, 14, and 21 of culture, the number of SS receptors amounted to 978 +/- 217, 3588 +/- 705, and 5865 +/- 3332 fmol/mg protein, respectively, whereas they were not measurable on day 0. From days 0-7, 7-14, and 14-21 of culture, octreotide (1 pM to 1 microM) inhibited PRL release and the intracellular PRL concentration, with IC50 values in the nanomolar range. However, no inhibition of cell growth was observed by these octreotide concentrations from day 0-7 of culture, while octreotide inhibited cell growth in a dose-dependent fashion from days 7-14 and 14-21 of culture (maximal inhibition by 25% and 26%, respectively). In a series of nine consecutive experiments we found a significant positive correlation between the percent inhibition of cell growth induced by 1 microM octreotide and the number of SS receptors on 7315b cells (r = 0.7865; P = 0.012). Inhibition of PRL release did not correlate with SS receptor numbers. Octreotide (1 microM) inhibited forskolin (0.5 microM)-stimulated cell growth and intracellular PRL concentrations, while in the presence of a high concentration of forskolin (10 microM), octreotide had no effect on forskolin-stimulated cell growth and intracellular PRL concentrations. In addition, its PRL release inhibitory effect was significantly lower in forskolin-stimulated cultures. Pretreatment of the cells with pertussis toxin (10 micrograms/liter) completely prevented the inhibition of cell growth by octreotide and diminished the inhibitory effect of octreotide on PRL release. Finally, 1 microM octreotide significantly inhibited forskolin-stimulated cAMP production (by 29% and 53% on days 7 and 14 of culture, respectively). We conclude that 1) octreotide inhibits 7315b rat pituitary tumor cell proliferation via a pertussis toxin-sensitive GTP-binding protein- and adenylate cyclase-dependent mechanism; and 2) the number of SS receptors on 7315b pituitary tumor cells may determine whether octreotide exerts a direct antiproliferative effect, whereas its antihormonal effect occurs in the presence of relatively low numbers of SS receptors. This suggests a dissociation of the antiproliferative and antihormonal effects induced by octreotide.
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PMID:Dissociation of antiproliferative and antihormonal effects of the somatostatin analog octreotide on 7315b pituitary tumor cells. 132 74

In GH3 cells and other clonal rat pituitary tumor cells, TRH has been shown to mediate its effects on prolactin release via a rise of cytosolic Ca2+ and activation of protein kinase C. In this study, we examined the role of protein kinase C in TRH-stimulated prolactin release from female rat primary pituitary cell culture. Both TRH and PMA stimulated prolactin release in a dose-dependent manner. When present together at maximal concentrations, TRH and PMA produced an effect which was slightly less than additive. Pretreatment of rat pituitary cells with 10(-6) M PMA for 24 hrs completely down-regulated protein kinase C, since such PMA-pretreated cells did not release prolactin in response to a second dose of PMA. Interestingly, protein kinase C down-regulation had no effect on TRH-induced prolactin release from rat pituitary cells. In contrast, PMA-pretreated GH3 cells did not respond to a subsequent stimulation by either PMA or TRH. Pretreatment of rat pituitary cells with TRH (10(-7) M, 24 hrs) inhibited the subsequent response to TRH, but not PMA. Forskolin, an adenylate cyclase activator, stimulated prolactin release by itself and in a synergistic manner when incubated together with TRH or PMA. The synergistic effects of forskolin on prolactin release was greater in the presence of PMA than TRH. Down-regulation of protein kinase C by PMA pretreatment abolished the synergistic effect produced by PMA and forskolin but had no effect on those generated by TRH and forskolin. sn-1,2-Dioctanylglycerol (DOG) pretreatment attenuated the subsequent response to DOG and PMA but not TRH. The effect of TRH, but not PMA, on prolactin release required the presence of extracellular Ca2+. In conclusion, the mechanism by which TRH causes prolactin release from rat primary pituitary cells is different from that of GH3 cells; the former is a protein kinase C-independent process whereas the latter is at least partially dependent upon the activation of protein kinase C.
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PMID:PMA-sensitive protein kinase C is not necessary in TRH-stimulated prolactin release from female rat primary pituitary cells. 145 79

Adenosine is a potent paracrine/autocrine feedback inhibitor of cell activation in a variety of tissues. Adenosine action was studied in pituitary cells, in which spontaneous electrical activity causes characteristic oscillations of the cytosolic free Ca2+ concentration, [Ca2+]i. Cells of the GH3B6 rat pituitary tumor line were studied by microspectrofluorimetry using the Ca2+ probes indo-1 and fura-2, in part in combination with electrophysiological tight seal whole cell recordings, obtained with the novel approach of patch perforation. It was demonstrated that adenosine receptor activation by N6-(R-phenyl-isopropyl)-adenosine (PIA) caused a block of electrical activity and abolished the ensuing alterations in [Ca2+]i. PIA mimicked the inhibitory action of somatostatin. Adenosine effects are mediated by A1 receptors in these cells and are antagonized by IBMX, an adenosine receptor blocker. PIA also suppressed action potentials that were elicited by the activation of protein kinase C with the phorbol ester PMA, or during the second phase of TRH action. In contrast, no interference was notable on TRH-induced intracellular Ca2+ mobilization. In addition to the abolition of Ca2+ transients, PIA lowers basal [Ca2+]i in some cells. It is proposed that in addition to the inhibition of adenylate cyclase, A1 receptor action on [Ca2+]i is an important element in the control of excitable pituitary cells.
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PMID:Adenosine A1 receptor-induced inhibition of Ca2+ transients linked to action potentials in clonal pituitary cells. 168 Jul 18

Functional somatostatin (SRIF, somatotropin release-inhibiting factor) receptors were expressed in Xenopus oocytes after injection of RNA isolated from the anterior pituitary tumor cell line AtT20. SRIF receptors were detected by measuring the ability of SRIF to inhibit cAMP formation stimulated by beta 2-adrenergic agonists in individual oocytes. beta 2-Adrenergic receptors (beta 2ARs) were expressed in oocytes by coinjecting RNA prepared by in vitro transcription of a beta 2AR cDNA clone with the pituitary cell RNA. Uninjected oocytes do not express detectable levels of either beta 2ARs or SRIF receptors. In oocytes coinjected with AtT20 and beta 2AR RNA, on the other hand, isoproterenol treatment led to a 2- to 3-fold increase in cAMP levels, whereas cotreatment with SRIF reduced this accumulation by 50-60%. The SRIF precursor somatostatin-28 and the cyclohexapeptide agonist MK678 also inhibited cAMP formation, whereas the biologically inactive N-terminal 14-amino acid fragment of somatostatin-28 was ineffective. The ability to detect changes in cAMP levels in individual oocytes may provide a simple procedure for the expression cloning of SRIF receptor cDNAs and other receptors functionally coupled to stimulation or inhibition of adenylate cyclase.
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PMID:Expression of functional pituitary somatostatin receptors in Xenopus oocytes. 168 51

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

Somatostatin and carbachol receptors are believed to be negatively coupled to adenylate cyclase in AtT-20 mouse pituitary tumor cells by an inhibitory guanine nucleotide-binding regulatory subunit. Activation of these receptors causes inhibition of cyclic AMP synthesis and adrenocorticotropin (ACTH) secretion stimulated by a variety of hormones. Secretion in response to several pharmacological agents, which do not increase AtT-20 cyclic AMP levels, is also antagonized by both somatostatin and carbachol. Inasmuch as ACTH secretion in response to all stimulants is dependent on extracellular calcium, the possibility that somatostatin and carbachol block calcium entry was investigated by observing the effects of these agents on the activity of the calcium channel activator, BAY-K-8644 [methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4- (2-trifluoromethylphenyl)-pyridine-5-carboxy-late] in AtT-20 cells. In first characterizing the effect of BAY-K-8644, it was noted that the channel agonist at 10(-10) to 10(-6) M itself rapidly increased basal ACTH secretion; higher concentrations (10(-4) M) reduced basal, (-)-isoproterenol, phorbol ester, 8-Br-cAMP and K+-stimulated secretion. BAY-K-8644 did not alter basal formation of cyclic AMP. The secretory response to BAY-K-8644 was dependent on extracellular calcium, and was inhibited by the calcium channel antagonist, nifedepine. When coapplied with (-)-isoproterenol, phorbol ester and 8-Br-cAMP, at a concentration which optimally stimulated ACTH secretion, BAY-K-8644 had an additive effect; the secretory responses to K+ (50 mM) or the calcium ionophore, A-23187, on the other hand, were potentiated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulation of adrenocorticotropin secretion from AtT-20 cells by the calcium channel activator, BAY-K-8644, and its inhibition by somatostatin and carbachol. 241 8

The report that ANF inhibits basal and CRF-stimulated adenylate cyclase activity in anterior pituitary homogenates suggested that the atrial peptide could inhibit ACTH secretion. This possibility was investigated in the ACTH-secreting AtT-20 mouse pituitary tumor cell line as well as homogenates or primary cell cultures from rat anterior hypophysis. ANF (up to 5 X 10(-7) M) was found to be completely ineffective in stimulating basal, CRF- and/or forskolin-stimulated adenylate cyclase activity, cAMP accumulation and ACTH secretion. Similarly, ANF had no effect on spontaneous or GRF-induced GH release from cells in primary culture. ANF receptors, however, are present in AtT-20 cells and anterior pituitary cells as evidenced by the ability of the peptide to stimulate intracellular cGMP accumulation. The data, therefore, suggests that ANF does not have a negative modulatory action on the secretory function of anterior pituitary. The role of cGMP in any other action(s) of ANF remains unknown.
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PMID:Atrial natriuretic factor does not affect basal, forskolin- and CRF-stimulated adenylate cyclase activity, cAMP formation or ACTH secretion, but does stimulate cGMP synthesis in anterior pituitary. 241 82

Regulation of GH gene expression by GRF involves cAMP as a second messenger. We have demonstrated that a 500-basepair fragment of the human GH (hGH) gene 5' flanking region can confer cAMP inducibility upon the chloramphenicol acetyltransferase transcription unit in transient transfections of rat pituitary tumor cells treated with forskolin, an activator of adenyl cyclase. The same hGH construct is not induced by forskolin in nonpituitary-derived cells. Experiments with hGH deletion constructs reveal that binding sites for transcription factor AP-2 and the pituitary-specific factor GHF-1 are not required for forskolin stimulation, but that GHF-1 may potentiate the effect. RNA analyses reveal that forskolin also stimulates accumulation of transcripts initiated at the hGH promoter. Other agents that elevate cAMP levels also stimulate hGH expression. Since the hGH 5' flanking region contains no sequences homologous to the cAMP-responsive element of the somatostatin gene, and the AP-2 sites do not appear to be required for the forskolin response, these results suggest that a novel cAMP-responsive element exists within 82 basepairs upstream from the transcriptional start of the hGH gene and that hGH regulation by GRF may involve interaction between a tissue-specific element and a cAMP-inducible element.
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PMID:Induction of human growth hormone promoter activity by the adenosine 3',5'-monophosphate pathway involves a novel responsive element. 254 55


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