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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extracts of rat anterior and intermediate-posterior pituitary were fractionated by sodium dodecyl sulfate polyacrylamide gel electrophoresis and assayed for immunoactive ACTH and endorphin. In both lobes the major forms of immunoactive ACTH have apparent molecular weights of 31,000 (31K), 20--21K, 14K, and 4.5K, and the major forms of immunoactive endorphin have apparent molecular weights of 31K (coincident with the peak of immunoactive ACTH), 13K (a betaLPH-like peptide), and 3.5K (a beta-endorphin-like peptide). However, the quantitative distribution of immunoactivity among the various forms differs greatly between the lobes. Assays using an extreme COOH-terminal ACTH antiserum indicate that the 31K ACTH/endorphin molecule in rat anterior and intermediate pituitary is similar to the pro-ACTH/endorphin molecule from mouse pituitary tumor cells. A radioimmunoassay that is specific for the NH2-terminal non-ACTH, nonendorphin segment (referred to as 16K fragment) of the mouse pro-ACTH/endorphin molecule was used to assay extracts of rat pituitary. In addition to detecting material at 31K and 20--21K, the 16K fragment radioimmunoassay detects significant amounts of cross-reactive material with an apparent molecular weight of 16K in extracts of both lobes. This result also suggests that the structure and processing of the rat 31K ACTH/endorphin molecule is similar to that of mouse tumor cell pro-ACTH/endorphin. Cell suspensions were prepared from the anterior and intermediate lobes of the rat pituitary and maintained in culture for a 24-h period. The isolated cells from both lobes incorporate [3H] phenylalanine into immunoprecipitable ACTH- and endorphin-containing molecules. By sequential immunoprecipitation with ACTH and endorphin antisera, it is possible to demonstrate directly that a single molecule (31K ACTH/endorphin) has antigenic determinants for both ACTH and endorphin. Significant amounts of 31K ACTH/endorphin are released into the culture medium by isolated anterior lobe and intermediate lobe cells. The isolated intermediate lobe cells synthesize and secrete relatively large amounts of a beta-endorphin-like molecule; the isolated anterior lobe cells secrete significant amounts of both a betaLPH-like molecule and a beta-endorphin-like molecule. These same quantitative differences between anterior and intermediate lobe tissue were observed in immunoassays of extracts of the separated lobes and probably reflect differences in the processing of the common precursor. The isolated anterior lobe cells can be stimulated to release increased amounts of immunoprecipitable ACTH and endorphin by incubation with a cyclic AMP analog and a phosphodiesterase inhibitor.
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PMID:Existence of a common precursor to ACTH and endorphin in the anterior and intermediate lobes of the rat pituitary. 8 77

The properties of adenylyl cyclase and cyclic nucleotide phosphodiesterases from GH-strains of rat pituitary tumor cells have been investigated. Adenylyl cyclase was inhibited by calcium ion and stimulated by fluoride ion, 5'-guanylylimidodiphosphate and by prior treatment of intact releasing hormone (TRH), which stimulates prolactin releasing hormone (TRH), which stimulates prolactin release and synthesis in GH-cells, did not cause a significant stimulation of adenylyl cyclase activity under a wide variety of assay conditions; under the same conditions, [3H]TRH bound to a previously characterized membrane receptor. GH-cells contain phosphodiesterase activity catalyzing the hydrolysis of cAMP which gives nonliner Lineweaver-Burk plots with apparent Km's for cAMP of 1.5 muM and 4mM. TRH did not affect the activity of cyclic nucleotide phosphodiesterase at high or low cAMP concentrations when added to broken cell preparations. Treatment of intact cells with TRH caused no changes in the total adenylyl cyclase and cyclic nucleotide phosphodiesterase activites within the first 2 h of incubation, when stimulation of prolactin release occurs, but did lead to slight decrease in adenylyl cyclase and the apparent low Km phosphodiesterase after 72 h of treatment.
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PMID:Adenylyl cyclase and cyclic nucleotide phosphodiesterases in GH-Strains of rat pituitary cells. 18 95

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 involvement of calmodulin in the secretion of beta-endorphin from the mouse anterior pituitary tumor cell line, AtT-20, was investigated. The calmodulin inhibitor W7 potentiated secretion produced by 8-BrcAMP, and induced a secretory response to arginine vasopressin, which did not elevate beta-endorphin levels when added alone. Release of hormone in response to CRF was not affected. Calmodulin phosphodiesterase inhibitor 8-MeOMeMIX produced a dose-dependent increase in 8-BrcAMP stimulation, suggesting that inhibition of cAMP degradation is the mechanism of enhancement of 8-BrcAMP-induced secretion in the presence of W7.
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PMID:Modulation of beta-endorphin secretion from mouse pituitary tumor cells by calmodulin inhibitor W7. 296 20

The AtT-20/D16-16 mouse pituitary tumor cell secretes corticotropin (ACTH) in response to corticotropin-releasing factor (CRF), (-)-isoproterenol, and vasoactive intestinal peptide (VIP). These responses are associated with a rapid increase in cyclic AMP formation. Somatostatin (SRIF) markedly decreases the stimulatory effect of CRF, (-)-isoproterenol, and VIP on both cyclic AMP formation and immunoreactive ACTH secretion. Forskolin and cholera toxin, adenylate cyclase activators, also stimulate cyclic AMP formation and ACTH secretion in AtT-20 cells and these responses are all inhibited by SRIF. The ACTH secretory responses to melittin and to the calcium ionophore A23187, neither of which increases cyclic AMP in AtT-20 cells, were not inhibited by SRIF. SRIF did not affect the binding of a tritiated beta-adrenergic receptor antagonist to AtT-20 membranes nor did it decrease basal cyclic AMP formation even in the presence of excess phosphodiesterase inhibitor, indicating that the reduction of cyclic AMP levels by SRIF did not involve either an interference with beta-adrenergic agonist binding to receptors or stimulation of cyclic AMP degradation. These results indicate that the inhibition of CRF-, (-)-isoproterenol-, and VIP-stimulated ACTH secretion by SRIF may be regulated by its inhibitory action on adenylate cyclase.
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PMID:Somatostatin inhibits multireceptor stimulation of cyclic AMP formation and corticotropin secretion in mouse pituitary tumor cells. 612 32

Addition of somatostatin (SRIF) inhibits corticotropin-releasing factor- and forskolin-stimulated cyclic AMP accumulation and adrenocorticotropin hormone secretion from mouse anterior pituitary tumor cells (AtT-20/D16-16). However, prior exposure of these cells to SRIF reduced the potency of SRIF to inhibit both corticotropin-releasing factor- and forskolin-stimulated cyclic AMP accumulation and adrenocorticotropin hormone release. This SRIF desensitization is time- and concentration-dependent and reversible. Cross-desensitization to SRIF analogs also occurred whereas SRIF pretreatment did not affect the inhibition by SRIF of 8-bromo-cyclic AMP-stimulated adrenocorticotropin hormone release or did it affect basal cyclic AMP levels, protein content or phosphodiesterase activity. These data indicate that SRIF can regulate the sensitivity of its own receptor and that SRIF desensitization may involve either a down-regulation of SRIF receptors or an uncoupling of these inhibitory receptors from adenylate cyclase.
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PMID:Somatostatin desensitization: loss of the ability of somatostatin to inhibit cyclic AMP accumulation and adrenocorticotropin hormone release. 614 43

Pertussis toxin (PT) modulation of the cyclic AMP (cAMP) accumulation induced by prostaglandin E1 (PGE1), cholera toxin (CT), and forskolin was used to study the role of cAMP in the regulation of prolactin release. The clonal cell line 235-1, derived from a rat anterior pituitary tumor, served as the major target tissue. While PT had no effect on basal cAMP levels, in the presence or absence of a phosphodiesterase inhibitor, this novel bacterial toxin potentiated the cAMP response to each stimulus. The PT enhancement of PGE1-stimulated cAMP production was maximal after 24 hr of PT exposure, whether the toxin was left in the medium or removed after as little as 30 sec. Although PGE1, CT, and forskolin are all secretagogues for prolactin, increasing release by about 50%, PT had no apparent effect on these responses. These data support the hypothesis that cAMP may facilitate prolactin release, but may not be the primary stimulus for secretion.
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PMID:Pertussis toxin actions on the pituitary-derived 235-1 clone: effects of PGE1, cholera toxin, and forskolin on cyclic AMP metabolism and prolactin release. 619 89

The responsiveness of anterior pituitary tumor (GH3) cells to promoters of prolactin secretion and/or synthesis and cyclic AMP accumulation was studied as a function of cellular Ca2+ content. GH3 cells exposed to media containing 1 mM ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid were reduced 7-fold in Ca2+ content without loss of viability. Preparations of Ca2+-depleted cells were largely unchanged in cyclic AMP content when challenged by thyrotropin-releasing hormone (TRH), whereas cells which were subsequently restored at optimal Ca2+ (0.5 mM) responded to the hormone with 2- to 3-fold increases in cyclic AMP content. The decreased responsiveness of Ca2+-depleted cells to TRH was not influenced by phosphodiesterase inhibitors, incubation time, or hormone concentration. TRH-dependent cyclic AMP accumulation was markedly potentiated by forskolin in Ca2+-restored, but not in Ca2+-depleted, cell preparations. Forskolin extended the time period during which cyclic AMP accumulated in response to TRH without altering the TRH concentration dependency of the cells. Varying increases in GH3 cyclic AMP content occurred in response to other hormones or agents which enhance prolactin secretion and/or synthesis. In Ca2+-restored cells, cyclic AMP content was increased 2-fold by prostaglandin E1 (PGE1) and epidermal growth factor (EGF), 10- to 15-fold by vasoactive intestinal polypeptide (VIP) and 6-fold by phorbol myristate acetate (PMA); the capacity of Ca2+-depleted cells, however, to accumulate cyclic AMP in response to PGE1, EGF, and VIP was greatly reduced. Accumulation of cyclic AMP following short-term incubations with cholera toxin similarly was dependent on Ca2+. Exposure of GH3 cells preloaded with 45Ca to TRH, PGE1, EGF, PMA, or VIP resulted in losses of cell-associated 45Ca. Pretreatment with these agents resulted in a decreased capacity of the cells to accumulate 45Ca from the extracellular medium. The results of this study support the hypothesis that various putative humoral regulators of prolactin secretion and/or synthesis act on GH3 cells to alter intracellular Ca2+ metabolism which in turn results in an increased cyclic AMP content through stimulation of adenylate cyclase activity.
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PMID:Regulation of Ca2+-dependent cyclic AMP accumulation and Ca2+ metabolism in intact pituitary tumor cells by modulators of prolactin production. 630 Jun 49

In recent years, remarkable progress has been made in the understanding of the pathogenesis of pituitary tumors. Pituitary tumors originate from the uncontrolled proliferation of a single transformed cell in which an initiating event has caused a gain of proliferative function. After the initiation, promoting factors cooperate in the clonal expansion. Common oncogenes, such as ras, are only exceptionally involved. The only activating mutations identified so far are gsp mutations causing the constitutive activation of cAMP pathway. However, gsp-positive adenomas are not associated to a more aggressive tumoral phenotype. The oncogenic potential of gsp mutations is limited by a more rapid degradation of the mutant Gs(alpha) with respect to the wild-type protein, and by a faster removal of cAMP due to increased phosphodiesterase activity. Estrogen-inducible gene sequences with transforming properties (pituitary tumor-transforming gene (PTTG)) have been identified in human pituitary tumors. Human pituitary tumor-transforming gene (hPTTG) is involved both in early pituitary tumorigenesis, as it causes in vitro and in vivo transformation acting as a transcription activator, and in tumor progression, as it regulates the production of basic fibroblast growth factor (bFGF), a potent activator of angiogenesis and mitogenesis. Moreover, a role of cyclin D1 in pituitary tumorigenesis is emerging. The allelic loss of loci for unknown oncosuppressor genes are currently under investigation, while an exceedingly limited role for menin gene and RB1 has been demonstrated for sporadic pituitary tumors. Abnormal methylation that predisposing toward genetic instability may favor the allelic loss or the reduced expression of oncosuppressor genes, is also an emerging field of investigation. Several promoting factors, including the excessive action of physiological stimulators, the defective action of inhibitors, the susceptibility to respond to inappropriate stimuli and the locally produced growth factors, help in tumor progression. The study of homeobox genes that intervene in pituitary cell differentiation may help in expanding our knowledge in pituitary tumor cell genealogy.
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PMID:Genesis of pituitary adenomas: state of the art. 1176 37

Although it is known that the expression of proopiomelanocortin, a precursor protein of adrenocorticotropic hormone, can be affected by a variety of drugs, the effects of calcium channel blockers have not been studied. This study examined the effect of calcium channel blockers on proopiomelanocortin gene expression. Mouse pituitary tumor cells stably transfected with approximately 0.7 kb of the rat proopiomelanocortin 5' promoter-luciferase fusion gene were stimulated by potassium chloride, corticotropin-releasing hormone (CRH) or forskolin, in the presence or absence of calcium channel blockers (nifedipine, verapamil and diltiazem). Assessments were made of proopiomelanocortin gene promoter activity and cyclic adenosine 3',5'-monophosphate (cyclic AMP) efflux. A dose-dependent enhancement of CRH- or forskolin-stimulated proopiomelanocortin promoter activity was observed with nifedipine and verapamil, but not diltiazem. Cyclic AMP efflux induced by CRH or forskolin was also enhanced by nifedipine and verapamil. In the presence of isobutylmethylxanthine, a phosphodiesterase inhibitor, enhancement of proopiomelanocortin promoter activity and cyclic AMP efflux by nifedipine and verapamil was not observed. It was concluded that the inhibition of phosphodiesterase is a probable mechanism for the effect of nifedipine and verapamil on CRH or forskolin induction of proopiomelanocortin gene expression.
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PMID:Potentiation of cyclic AMP-mediated proopiomelanocortin gene promoter activity by calcium channel blockers in a pituitary cell line. 1719 58


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