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)

Transforming growth factor-beta 1 (TGF-beta 1) and TGF-beta 2 were found to be potent mitogens for purified rat Schwann cells, each stimulating DNA synthesis in quiescent cells and also increasing their proliferation rate. Half-maximal stimulation of DNA synthesis occurred at approximately 0.1 ng/ml TGF-beta 1 or TGF-beta 2. Mitogenic stimulation by TGF-beta 1 and TGF-beta 2 was enhanced by forskolin, which activates adenylate cyclase, at concentrations up to 0.5 microM forskolin. However, at 5 microM forskolin, the synergistic interaction between forskolin and TGF-beta 1 was abolished. These results are in contrast to the observed synergy between forskolin and another Schwann cell mitogen, glial growth factor (GGF). Both 0.5 and 5 microM forskolin were found to enhance the stimulation of DNA synthesis by partially purified GGF (GGF-CM). As well as being functionally distinct, TGF-beta 1 and GGF-CM activities were also physically separable by chromatography on a Superose 12 gel permeation column. Thus, TGF-beta 1 and beta 2 are rat Schwann cell mitogens, and Schwann cells are one of the few normal cell populations to respond mitogenically to TGF-beta.
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PMID:Transforming growth factors-beta 1 and beta 2 are mitogens for rat Schwann cells. 255 56

The effects of protein kinase C (PKC) stimulation with phorbol dibutyrate, PDBu, were determined on transepithelial net Cl- transport (Isc) across the isolated bullfrog cornea. Between 1 nM and 1 microM, PDBu had no effect on either the Isc or the conductance, gt, as well as the membrane voltage (Vsc) but it decreased the fractional apical membrane resistance (fR0). PDBu caused a dose-dependent decline and reversal of the stimulatory effect of the mixed alpha and beta adrenergic agonist, epinephrine, on the Isc. With 1 microM PDBu, 100 microM epinephrine decreased the Isc by 20% below its control value. As without PDBu, epinephrine decreased fR0 and depolarized the Vsc. Evidence that this reversal by PDBu stems from a selective stimulation of PKC is: (1) neither its vehicle nor the inactive phorbol analog, 4 alpha-phorbol didecanoate, PDD (1 microM), decreased either the fR0 or altered the stimulatory effect of epinephrine on the Isc. (2) After preincubation with 30 microM H-7, which inhibited PKC stimulation in subcellular membrane and cytosolic fractions of frog corneal epithelium, the stimulatory effect of epinephrine on the Isc was unchanged by 1 microM PDBu. Preincubation with PDBu completely inhibited the stimulatory effect of the beta adrenergic agonist, isoproterenol (10 microM), on the Isc but did not affect the stimulatory effect of 1 microM forskolin on the Isc, indicating that PKC stimulation results in uncoupling of adrenergic regulation of adenylate cyclase activity. Epinephrine did not reverse the Isc in corneas that were preincubated with either the alpha 2- -adrenergic antagonist, yohimbine (100 microM), or the general alpha adrenergic antagonist, phenoxybenzamine (100 microM). With yohimbine, epinephrine had no effect on the Isc whereas with phenoxybenzamine the stimulation by epinephrine was fully restored. These effects suggest that stimulation of PKC is dependent upon the stimulation of alpha 1-adrenergic receptors by epinephrine as well as the presence of PDBu. Reversal and stimulation of the Isc by epinephrine were both associated with a depolarization of the Vsc and similar decreases in fR0. These similar effects on fR0 suggest that PKC stimulation as well as alpha 2 adrenergic activation by epinephrine are associated with increases in basolateral membrane resistance.
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PMID:Reversal of the epinephrine stimulation of Cl- transport in bullfrog cornea by phorbol esters. 259 91

Functional gastrin-containing tumor cells (GT cells) have been maintained in short-term culture on microporous membranes, and their response to selected agents has been determined. After dispersion of gastrinoma by collagenase-DNAase digestion coupled with mechanical disruption, dispersed cells were depleted in stromal material by selective attachment to a plastic substrate, then cultured for 72 hours on porous cellulose membranes. Cultures contained 68 +/- 5% GT cells with a viability of 92 +/- 2%. Secretin stimulated the rate of gastrin release from cultured GT cells in both a time- and a dose-dependent fashion. To examine the possible involvement of adenylate cyclase- and protein kinase C-mediated mechanisms in regulating gastrin release from the neoplastic GT cells, we evaluated the effects of 8-bromoadenosine 3':5'-cyclic monophosphate (8-BrcAMP; 10(-4) - 10(-2) mol/L), the diterpene forskolin (10(-5) mol/L), 12-0-tetradencanoylphorobol 13-acetate (TPA; 10(-8) - 10(-6) mol/L), and 4 alpha-phorbol 12,13-didecanoate (4 alpha PDD; 10(-8) - 10(-6) mol/L) on gastrin release. Among all compounds tested, 8-BrcAMP (10(-2) mol/L) was the most potent, stimulating the rate of gastrin release 263% above basal. Both 8-BrcAMP and TPA stimulated gastrin release in a dose-dependent fashion. The biologically inactive phorbol ester, 4 alpha PDD, was without effect at all concentrations. Somatostatin (10(-8) - 10(-6) mol/L) inhibited 8-BrcAMP-stimulated gastrin release in a dose-dependent fashion to a maximum of 75%.
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PMID:Control of gastrin release in cultured gastrinoma-derived G cells. 289 16

The phorbol ester 12-O-tetradecanoyl phorbol 13-acetate (TPA) enhances the effects of TRH on phase II of prolactin secretion as well as on hormone synthesis at both low and high TPA receptor occupancy. Furthermore TPA, but not the biologically inactive substance 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD), stimulates the particulate bound adenylate cyclase with a time course paralleling that of TRH activation. However, the combined additions of TRH and TPA activate this cyclase in an additive manner while the Gpp(NH)p- and the forskolin-sensitive enzyme are unaffected by TPA addition. Polymyxin B, which inhibits protein kinase C, abolishes activation of adenylate cyclase by TPA without interfering with the stimulatory action of TRH. Also, when phosphatase activity is preferentially inhibited by pretreatment of the cells with sodium vanadate, the TRH-sensitive cyclase is unaltered, while TPA activation is obliterated. Maximal stimulation of adenylate cyclase by cholera toxin pretreatment, obliterated the actions of TRH and TPA. Cells pretreated with pertussis toxin retained their TRH-sensitive cyclase, however, TPA-responsiveness was lost. We therefore suggest that the action of TPA as it relates to activation of adenylate cyclase, is probably mediated via the Gi component of the adenylate cyclase complex, while TRH stimulates the enzyme via the classical pathway involving the stimulatory GTP binding protein (Gs).
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PMID:Phorbol esters and thyroliberin have distinct actions regarding stimulation of prolactin secretion and activation of adenylate cyclase in rat pituitary tumour cells (GH4C1 cells). 290 8

The effect of phorbol-12-myristate-13-acetate (PMA), an activator of protein kinase C (PK-C) on lipid peroxidation (LPO) in rat liver homogenates and microsomes was studied. PMA (10(-10) to 10(-6) M) produced a concentration-dependent inhibition of LPO, which was greatly decreased by polymyxin B (PxB) (an inhibitor of PK-C). The non-active analogue of PMA, 4 alpha-phorbol-12,13-didecanoate (4 alpha-PDD) exerted no inhibitory effect. The adenylate cyclase activator, forskolin (FK) (10(-6) M) abolished the inhibitory effect of PMA on LPO. PMA and FK did not inhibit LPO in liposomes. It is suggested that LPO in biomembranes could be regulated by PK-C, whose inhibitory effect might be prevented by cAMP-dependent protein kinases.
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PMID:The role of secondary messengers in the regulation of lipid peroxidation in rat liver microsomes. 323 56

Growth of thyroid cancer cells is stimulated by various growth factors via signal transduction pathways. TSH, EGF, IGF, and TGF-alpha stimulate and TGF-beta inhibits thyroid cell growth. TSH stimulates thyroid cells via both the adenylate cyclase-PKA and the PLC-PKC-Ca signal transduction pathways. TSH-r, ras, gsp, ret, trk, and myc are oncogenes that are activated in some thyroid neoplasms. P53 and RB are tumor suppressor genes that are inactivated in some thyroid cancers.
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PMID:Thyroid growth factors, signal transduction pathways, and oncogenes. 774 50

The present studies examine the effect of transforming growth factor-beta 1 (TGF-beta 1) on signal transduction pathways in two cultured renal epithelial cell lines. TGF-beta 1 promotes basal and agonist-stimulated adenylate cyclase activity in LLC-PK1 but not MDCK cell membranes. TGF-beta 1 stimulation of LLC-PK1 membrane adenylate cyclase activity occurs quickly and can be attenuated by pertussis toxin pretreatment. Both TGF-beta 1 and adenosine 3',5'-cyclic monophosphate (cAMP) exert comparable effects on [3H]thymidine uptake in LLC-PK1 cells, suggesting that TGF-beta 1 regulation of adenylate cyclase activity potentially plays a role in mediating biological responses to TGF-beta 1. The activities of protein kinase C and phospholipase A are not affected by TGF-beta 1 in either LLC-PK1 or MDCK cells. Both TGF-beta 1 and epidermal growth factor (EGF) increase expression and induce the appearance of new forms of the cAMP response element binding protein (CREB) in LLC-PK1 cells. These effects of TGF-beta 1 and EGF on CREB appear to be specific since neither TGF-beta 1 nor EGF alters expression of an activating transcription factor in LLC-PK1 cells. The effect of TGF-beta 1 and EGF to alter expression of CREB does not affect CREB binding to its regulatory element in LLC-PK1 cell lysates. These results suggest that some of the biological effects of TGF-beta 1 may be attributed to stimulation of adenylate cyclase activity and cAMP formation as well as to enhanced expression and/or modification of the CREB transcription factor in LLC-PK1 cells.
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PMID:Transforming growth factor-beta 1 regulation of signal transduction in two renal epithelial cell lines. 823 88

Myocardial dysfunction following prolonged ischemia and reperfusion is at least partially dependent upon adhesion of neutrophils to myocardial and endothelial cells. Neutrophils are thought to contribute to reperfusion injury by two mechanisms: impairment of the microvasculature by physical obstruction, and secretion of products that damage microvasculature and myocardium. Cytokines have been shown to play several roles in neutrophil aggregation. Interleukin-6 (IL-6), along with IL-1 and tumor necrosis factor-alpha (TNF-alpha), induces the expression of intracellular adhesion molecule-1 (ICAM-1) in myocytes and endothelial cells, respectively. These cytokines also inhibit contractility and nitric oxide release (a vasodilator), and IL-1 and TNF-alpha have been found to reduce adrenergic stimulation of myocardial contractility by reducing intracellular cyclic AMP levels and uncoupling adenylate cyclase from beta receptors. The transforming growth factors, TGF-alpha and TGF-beta, also have a role in reperfusion injury. TGF-alpha reduces endothelial cell release of nitric oxide, while TGF-beta appears to protect against reperfusion injury by reducing plasma TGF-alpha levels, blocking neutrophil adherence, and promoting nitric oxide release. Although cytokines are likely to have important roles in reperfusion injury, their involvement in myocardial stunning is unclear.
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PMID:Cytokines and reperfusion injury. 846 22

To determine whether the adenylate cyclase and the protein kinase C pathways act independently to modulate the human sperm acrosome reaction, we studied the effects of 2'-O-methyladenosine (adenylate cyclase inhibitor) on acrosome reactions induced by protein kinase C activators (phorbol diesters and synthetic diacylglycerols) or an adenylate cyclase stimulator (forskolin:FR). Fifty aliquots of capacitated spermatozoa were divided into 5 groups (A, B, C, D, and E), each containing 10 samples. One control aliquot (CN) and five experimental aliquots (EX1, EX2, EX3, EX4, and EX5) were prepared from each sample. Phorbol 12-myristate, 13-acetate (PMA, 10 mumol/L), 4 beta-phorbol 12,13-didecanoate (PDD, 0.1 mumol/L), 1-oleoyl-2-acetyl-sn-glycerol (OAG, 50 mumol/L), 1,2-dioctanoyl-sn-glycerol (DOG, 50 mumol/L), or FR (10 mumol/L) was added to each of the experimental aliquots in groups A, B, C, D, and E, respectively. Increasing concentrations of 2'-O-methyladenosine were added to aliquots EX2, EX3, EX4, and EX5. After an incubation period of 25 min at 37 degrees C, it was found that the percentage of acrosome-reacted spermatozoa (%ARS) was significantly and dose-dependently decreased by 2'-O-methyladenosine concentrations of 1 mM or more. Within each group, the %ARS was significantly higher in EX1 aliquots than in CN aliquots. The reduction of acrosome reactions induced by protein kinase C activators by the adenylate cyclase inhibitor suggests that the protein kinase C pathway interacts with the adenylate cyclase pathway to modulate the human sperm acrosome reaction.
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PMID:Effects of an inhibitor of adenylate cyclase on acrosome reaction induced by protein kinase C activators. 847 Sep 45

This study examined inositol phosphate and cAMP regulation by TGF-beta 1, -beta 2 and -beta 3 in normal and tumour-derived human oral keratinocytes. Previous findings indicated that the cell lines expressed TGF-beta cell surface receptors and had a range of response to exogenous TGF-beta 1, -beta 2 and -beta 3 from being refractory to the ligand to marked inhibition. Basal levels of inositol phosphates broadly reflected the differentiation status of the cells as demonstrated by involucrin expression, but did not correlate with responsiveness to TGF-beta 1, as measured previously by thymidine incorporation. Treatment of cells with bradykinin or serum caused up-regulation of inositol phosphate levels; by contrast, TGF-beta 1, -beta 2 and -beta 3 failed to modulate inositol phosphates. In two tumour-derived cell lines, the TGF-beta isoforms had no effect on cAMP levels, despite a significant increase in cAMP using a potent agonist of adenylate cyclase (forskolin). Furthermore, the cAMP analogue, dibutyryl cAMP, failed to mimic the inhibitory or refractory responses of TGF-beta in these cells lines. The results demonstrate that in normal and tumour-derived human oral keratinocytes, TGF-beta signal transduction is not mediated by inositol phosphates or cAMP.
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PMID:TGF-beta isoforms fail to modulate inositol phosphates and cAMP in normal and tumour-derived human oral keratinocytes. 860 68


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