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: UNIPROT:P01189 (beta-endorphin)
21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During cellular senescence, non-clonal cultures of bovine adrenocortical cells show a continuous decline in the rate of production of cyclic AMP (cAMP) stimulated by adrenocorticotropin (ACTH), without changes in the rate of forskolin- or prostaglandin E1-stimulated cAMP production. We investigated the possible mechanisms for loss of response to ACTH by examining the properties of clones of bovine adrenocortical cells. ACTH-stimulated cAMP production rates were measured in clones immediately after isolation, during long-term growth following isolation, and after subcloning. ACTH-stimulated rates were compared with cAMP production in response to forskolin, which acts directly on the catalytic subunit of adenylate cyclase. The results show that cloning is not necessarily associated with a loss of response to ACTH, but that clones with high ACTH response can give rise to subclones with low response. Clones of adrenocortical cells, at the same approximate population doubling level (PDL), showed ACTH response levels that ranged from 12 to 135 pmol cAMP/10(6) cells/min, whereas mass cultures at this PDL showed approximately 50 pmol/10(6) cells/min. Forskolin-stimulated cAMP production rates in clones varied only over the range of 59-119 pmol/10(6) cells/min and showed no correlation with the ACTH-stimulated rates. All clones were adrenocortical cells, as shown by mitogenic response to angiotensin II and cAMP-inducible 17 alpha-hydroxylase activity. The replicative potential of clones varied widely, and there was no apparent correlation between ACTH response levels and growth potential. The level of ACTH response in each clone was stable during proliferation through at least 25 PD beyond the stage at which the clone was isolated. When clones were subcloned, a clone with a high ACTH response level produced sister subclones that had ACTH response levels ranging from 3% of that of the parent clone to a level slightly greater than that of the parent clone. The growth potential of sister subclones varied widely, as for the parent clones, and there was no obvious correlation between growth potential and ACTH response. Two subclones were cloned; in sub-subclones, levels of ACTH response were again different from each other and also from the parent subclone; in one case, the level of ACTH response was approximately eight-fold higher than that of the parent subclone. These experiments show that clonal variation in the extent of expression of a differentiated property may occur in a normal differentiated cell in culture. The loss of ACTH response and the loss of proliferative potential appear to be independent stochastic events.
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PMID:Clonal variation in response to adrenocorticotropin in cultured bovine adrenocortical cells: relationship to senescence. 302 4

alpha-MSH-induced pigment dispersion in melanophores shows an absolute requirement for extracellular Ca2+. To localize Ca2+ sites involved in the mechanism of action of alpha-MSH we studied the effects of Ca2+ deprivation on alpha-MSH and forskolin-induced melanophore responses. In an in vitro melanophore system employing ventral tailfins of Xenopus tadpoles, melanophore responses were assayed in terms of pigment dispersion and the phosphorylation state of a 53 kDa melanophore-specific protein. In the same melanophore system alpha-MSH has been shown to specifically increase the phosphorylation of this 53 kDa protein. Forskolin induces a dose-dependent pigment dispersion (EC50 7 X 10(-7) M). In contrast to the dispersion induced by alpha-MSH forskolin-induced dispersion does not require extracellular Ca2+. Moreover, in a Ca2+-free medium melanophores with permanently activated MSH-receptors aggregate, but can be redispersed by the addition of forskolin. Forskolin increases 53 kDa phosphorylation in a dose-dependent manner. Maximal stimulation with forskolin (10(-5) M) is four-fold and equals maximal 53 kDa phosphorylation obtainable with alpha-MSH. The MSH-induced increase in 53 kDa phosphorylation is inhibited by Ca2+ deprivation, whereas the forakolin-induced increase is unaffected. Our results suggest that alpha-MSH and forskolin stimulate melanophores through a common pathway and confirm that cAMP is a second messenger in alpha-MSH action in this system. We conclude that the Ca2+ sites in the mechanism of alpha-MSH action on melanophores precede adenylate cyclase activation.
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PMID:Calcium requirement for alpha-MSH action on melanophores: studies with forskolin. 609 71

Forskolin reduced the plating efficiency of Y1 adrenocortical tumor cells in a concentration-dependent manner--more than 5-orders of magnitude at 10 uM forskolin and at least 6-orders of magnitude at 50 uM forskolin. This effect was related to the diterpene's ability to increase adenylate cyclase activity and adenosine 3',5'-monophosphate (cAMP) levels in Y1 cells. Stable, forskolin-resistant mutants were isolated following growth of Y1 cells for 3 to 4 weeks in the presence of 10 uM forskolin. These mutants were stable, were present in the population at a ratio of approximately 15 mutants per million cells and appeared to result from a defect in cAMP accumulation rather than cAMP action. The forskolin-resistant phenotype was associated with a reduced ability of forskolin to stimulate adenylate cyclase activity in intact cells and in cell homogenates. The adenylate cyclase system of forskolin-resistant mutants was responsive to NaF, but was virtually insensitive to corticotropin (ACTH). As determined by a modified fluctuation analysis, the forskolin-resistant phenotype arose by spontaneous mutation at a frequency consistent with a mutational event at a single genetic locus (2 mutants per million cells per generation). These results indicate that the mutation which rendered Y1 cells insensitive to ACTH likely was the same as that which led to forskolin-resistance. Furthermore, the mutation seemed to behave dominantly. Although the gene product altered by the mutation is unknown, it does not appear to be the catalytic subunit of the enzyme.
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PMID:Analysis of the mutation to forskolin-resistance in Y1 adrenocortical tumor cells. 610 Feb 48

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

Stimulation of beta adrenergic receptors on AtT-20 cells increases intracellular cyclic AMP levels and adrenocorticotropin hormone (ACTH) release. Pretreatment of these cells with catecholamines reduces the ability of (-)-isoproterenol to stimulate both cyclic AMP formation and ACTH secretion. This beta receptor desensitization is time- and dose-dependent and is reversible. Various beta adrenergic agonists can induce this desensitization with a rank order of potency of salmefamol greater than or equal to (-)-isoproterenol greater than or equal to epinephrine greater than or equal to norepinephrine greater than or equal to (+)-isoproterenol. (+/-)-Propranolol but not practolol can block the (-)-isoproterenol-induced beta receptor desensitization. Long-term treatment of AtT-20 cells with (-)-isoproterenol reduces the density of beta receptors but does not affect the affinity of these sites for [3H]dihydroalprenolol. In addition to desensitizing beta receptors, (-)-isoproterenol pretreatment enhances basal ACTH secretion. This effect was dose-dependent and blocked by (+/-)-propranolol. Forskolin-stimulated cyclic AMP formation and ACTH secretion was not altered by (-)-isoproterenol treatment indicating that the desensitization of beta receptors on AtT-20 cells is the result of receptor-adenylate cyclase uncoupling. No cross-desensitization of corticotropin releasing factor or vasoactive intestinal peptide receptors occurred as (-)-isoproterenol treatment did not alter the effect of these peptides on cyclic AMP synthesis or ACTH secretion.
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PMID:Desensitization of beta adrenergic receptors linked to adrenocorticotropin secretion. 613 52

The effects of forskolin, an adenylate cyclase activator, were investigated on adrenocorticotropin (ACTH) secretion from AtT-20/ D16 -16 mouse pituitary tumor cells. Forskolin increased adenylate cyclase activity in these cells in the absence of added guanyl nucleotide, an effect blocked by somatostatin. Cyclic AMP synthesis and ACTH secretion increased in a concentration-dependent manner, not only in the clonal cells, but in primary cultures of rat anterior pituitary as well. Somatostatin inhibited cyclic AMP synthesis and ACTH secretion in response to forskolin. When forskolin was coapplied with corticotropin releasing factor, cyclic AMP synthesis was potentiated and ACTH secretion additive. The calcium channel blocker, nifedipine, inhibited forskolin, and 8-bromocyclic AMP stimulated ACTH secretion. These data suggest that ACTH secretion may be regulated at the molecular level by changes in cyclic AMP formation, which in turn regulate a calcium gating mechanism.
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PMID:Forskolin stimulates adenylate cyclase activity, cyclic AMP accumulation, and adrenocorticotropin secretion from mouse anterior pituitary tumor cells. 614 27

Forskolin, a unique diterpene which directly activates the adenylate cyclase, stimulated production of both cyclic AMP and corticosterone in isolated rat adrenal cells, in vitro. This agent also potentiated the action of adrenocorticotropin and/or cholera toxin on cyclic AMP production and steroidogenesis at lower concentrations. It augmented both an early (cyclic AMP production) and a late (steroidogenesis) action of the hormone in the adrenal gland.
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PMID:Forskolin potentiates adrenocorticotropin-induced cyclic AMP production and steroidogenesis in isolated rat adrenal cells. 628 44

Pretreatment of rat anterior pituitary cells with corticotropin releasing factor (CRF) rapidly and markedly reduced the ability of CRF to restimulate cyclic AMP formation and adrenocorticotropic hormone (ACTH) release. The effect was dependent on the length of time of pretreatment as well as the concentration of CRF. Neither basal nor intracellular immunoreactive ACTH levels nor basal cyclic AMP content were affected. CRF's stimulatory action on cyclic AMP formation and ACTH release recovered within one hour following CRF pretreatment. Forskolin, a compound that directly activates adenylate cyclase also releases ACTH from these cells. Pretreatment with CRF did not alter forskolin-stimulated cyclic AMP accumulation or ACTH secretion. Furthermore, CRF pretreatment did not change epinephrine's ability to increase the release of ACTH. These results indicate that CRF can regulate the responsiveness of its own receptor.
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PMID:Desensitization of corticotropin-releasing factor receptors. 630 92

Forskolin is an activator of adenylate cyclase in many cell types. In order to determine the mechanism of forskolin's action and to determine if this mechanism is shared by hormones and other agonists of the adenylate cyclase system, we isolated and partially characterized several spontaneous, forskolin-resistant mutants from the Y1 mouse adrenocortical tumor cell line. Forskolin increased adenylate cyclase activity in Y1 cell homogenates approximately 30-fold. By virtue of its effect on cAMP accumulation, forskolin (10 microM) also inhibited the growth of Y1 cells in monolayer culture. Using forskolin as a selective agent, spontaneous mutants capable of growth in the presence of 10 microM forskolin were isolated from the Y1 cell line at a frequency of 1-2/10(6) cells. In these mutants, resistance was stable, resulting from a defect in cAMP accumulation rather than cAMP action, and was associated with a reduced ability of forskolin to stimulate adenylate cyclase activity in cell homogenates. Whereas corticotropin stimulated adenylate cyclase activity over 35-fold in cell homogenates from the Y1 parent, ACTH had only marginal effects on the enzyme's activity in the mutant clones. Fluoride-stimulated adenylate cyclase activity seemed unimpaired. These results suggest that the resistance to forskolin resulted from a mutation in the adenylate cyclase system, not in the catalytic subunit, but at a locus related to the ACTH.
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PMID:Isolation of forskolin-resistant adrenal cells defective in the adenylate cyclase system. 653 78

Corticotropin (ACTH) binds to specific receptors in the adrenal cortex and thereby regulates glucocorticoid and mineralocorticoid production. The number of ACTH binding sites on adrenocortical cells is increased by exposure of cells to activators of the cAMP pathway. The mechanism responsible for the increase in ACTH binding sites is not known. We therefore studied the levels of ACTH-R mRNA in mouse Y-1 and human NCI-H295 (H295) adrenocortical carcinoma cell lines. ACTH induced an increase in mouse ACTH-R mRNA in Y-1 cells that was time and dose dependent, increasing 6-fold over basal levels following exposure to 10(-8) M ACTH for 19-24 h. The amount of human ACTH-R mRNA in H295 cells increased 2-4-fold following a 24 h exposure to 10(-8) M ACTH, 1 mM dbcAMP, or 10(-5) M Forskolin. Treatment of H295 cells with angiotensin II (A-II) was found to dramatically increase the level of ACTH-R mRNA. These data indicate that regulation of ACTH-R mRNA levels is at least one mechanism by which ACTH and A-II elevate the number of ACTH binding sites in the adrenocortical cells.
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PMID:ACTH induces up-regulation of ACTH receptor mRNA in mouse and human adrenocortical cell lines. 818 50


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