Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many hormones act on neuroendocrine cells by activating second messenger pathways. Two of these, the phosphoinositol and cAMP-dependent pathways, cause changes in cellular activity through specific protein kinases. By phosphorylating cytoplasmic and nuclear proteins, these kinases apparently coordinate cellular processes, including the biosynthesis and release of neuropeptides. Somatostatin biosynthesis and release, for example, are both positively regulated by the second messenger cAMP in hypothalamic cells, and cAMP also induces somatostatin gene transcription 8-10-fold in transfected PC12 pheochromocytoma cells. Transcriptional induction requires a 30-nucleotide cAMP response element (CRE) which is conserved in other cAMP-responsive genes. This element also confers cAMP responsiveness when placed upstream of the heterologous simian virus 40 (SV40) promoter. The somatostatin gene does not, however, respond to cAMP in mutant PC12 cells which lack cAMP-dependent protein kinase type II activity. Activation of somatostatin gene transcription may consequently require the phosphorylation of a nuclear protein which binds to the CRE. Using a DNase I protection assay, we have characterized a nuclear protein in PC12 cells which binds selectively to the CRE in the somatostatin gene. We have purified this protein which is of relative molecular mass 43,000 (Mr 43K) by sequence-specific DNA affinity chromatography. This 43K CRE binding protein (CREB) is phosphorylated in vitro when it is incubated with the catalytic subunit of cAMP-dependent protein kinase. Stimulating PC12 cells with forskolin, an activator of adenyl cyclase, causes a 3-4-fold increase in the phosphorylation of this protein. We conclude that the cAMP-dependent pathway may regulate gene transcription in response to hormonal stimulation by phosphorylating this CREB protein.
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PMID:Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. 288 56

In order to identify the transcription factors that may be involved in the development and differentiation of rat Schwann cells we examined the expression of c-Jun, Jun B, Jun D and the cAMP response element binding protein (CREB) in vivo and in vitro. We found that CREB was expressed at high levels throughout nerve development by both Schwann cells and their precursors. Jun family members, on the other hand, were expressed only at low levels in a few nuclei of the developing nerve. After sciatic nerve transection, however, c-Jun levels were rapidly up-regulated in many Schwann cells of the distal stump but CREB, Jun B and Jun D levels were not affected. When nerve contact was resumed after crush injury c-Jun levels returned to control values. Interestingly, unlike the situation in vivo, when Schwann cells were removed from the nerve and cultured, levels of all three Jun family members were rapidly up-regulated. This also occurred in Schwann cell precursors. In other experiments we found that Schwann cell c-Jun, but not Jun B or Jun D, expression was down-regulated by the adenylate cyclase activator, forskolin. In addition, we show that the forskolin induced down-regulation of c-Jun is not necessary for Schwann cell proliferation or myelination to occur.
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PMID:Expression of c-Jun, Jun B, Jun D and cAMP response element binding protein by Schwann cells and their precursors in vivo and in vitro. 758 11

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

A-kinase anchor protein 75 (AKAP75) binds regulatory subunits (RIIalpha and RIIbeta) of type II protein kinase A (PKAII) isoforms and targets the resulting complexes to sites in the cytoskeleton that abut the plasma membrane [1-7]. Co-localization of AKAP75-PKAII with adenylate cyclase and PKA substrate/effector proteins in cytoskeleton and plasma membrane effects a physical and functional integration of up-stream and downstream signaling proteins, thereby ensuring efficient propagation of signals carried by locally generated cyclic AMP (cAMP) [4-9]. An important, but previously untested, prediction of the AKAP model is that efficient, cyclic nucleotide-dependent liberation of diffusible PKA catalytic subunits from cytoskeleton-bound AKAP75-PKAII complexes will also enhance signaling to distal organelles, such as the nucleus. We tested this idea by suing HEK-A75 cells, in which PKAII isoforms are immobilized in cortical cytoskeleton by AKAP75. Abilities of HEK-A75 and control cells (with cytoplasmically dispersed PKAII isoforms) to respond to increases in cAMP content were compared. Cells with anchored PKAII exhibited a threefold higher level of nuclear catalytic subunit content and 4-10-fold greater increments in phosphorylation of a regulatory serine residue in cAMP response element binding protein (CREB) and in phosphoCREB-stimulated transcription of the c-fos gene. Each effect occurred more rapidly in cells containing targeted AKAP75-PKAII complexes. Thus, anchoring of PKAII in actin cortical cytoskeleton increases the rate, magnitude and sensitivity of cAMP signaling to the nucleus.
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PMID:A-kinase anchor protein 75 increases the rate and magnitude of cAMP signaling to the nucleus. 938 44

The neurotransmitter dopamine (DA) stimulates neurite outgrowth and growth cone formation in cultures of embryonic rat striatum through activation of D1 but not D2 receptors. We show here that neurite outgrowth could be stimulated to a similar extent by elevating cellular cAMP levels. Second, the neuritotrophic effect of DA was completely abolished by inhibiting adenylate cyclase or protein kinase A (PKA) but not protein kinase C (PKC). Third, double staining of cultures with antibodies against growth-associated protein-43 (GAP-43) and the phosphorylated form of the cAMP response element binding protein (pCREB) showed that pCREB was nearly exclusively associated with GAP-43-positive, i.e., actively growing, neurons. Again, this effect depended on D1 receptor and PKA activation. Although cross-talk with other signaling pathways needs to be studied further, we conclude that DA promotes the differentiation of striatal neurons via stimulation of D1 receptors and the cAMP/PKA signal transduction pathway.
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PMID:Differentiative effects of dopamine on striatal neurons involve stimulation of the cAMP/PKA pathway. 960 29

Transforming growth factors beta (TGFbeta) and cyclic AMP (cAMP) both participate in growth and differentiation of the developing mammalian secondary palate and elicit similar biological responses. Cross-talk between these two signal transduction pathways in cells derived from the embryonic palate has been demonstrated previously. In the present study, we have examined nuclear convergence of these signalling pathways at the level of transcriptional complex formation. Biotinylated oligonucleotides encoding a consensus Smad binding element (SBE), or a cyclic AMP response element (CRE), were mixed with cell extracts from murine embryonic palate mesenchymal (MEPM) cells that were treated with either TGFbeta or forskolin. Protein-oligonucleotide complexes were precipitated with streptavidin-agarose, and analysed by Western blotting to identify proteins in the complex bound to each consensus oligonucleotide. TGFbeta treatment of MEPM cells increased the levels of phosphorylated Smad2, phosphorylated cAMP response element binding protein (CREB), and the coactivator, CREB binding protein (CBP), that were part of a complex bound to the SBE. Treatment of cells with forskolin, a stimulator of adenylate cyclase, increased the amount of phosphorylated CREB and CBP, but not the amount of phosphorylated Smad2 bound in a complex to the SBE. Additionally, the presence of the co-repressors, c-Ski and SnoN, was demonstrated as part of a complex bound to the SBE (but not the CRE). Amounts of c-Ski and SnoN found in the SBE-containing complex increased in response to either TGFbeta or forskolin. These results demonstrate that phosphorylated CREB forms a complex with the co-activator CBP, phosphorylated Smad2 and the co-repressors c-Ski and SnoN on a consensus SBE. This suggests cooperative regulation of genes with SBE-containing promoters by the cAMP and TGFbeta signalling pathways in the developing palate.
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PMID:Nuclear convergence of the TGFbeta and cAMP signal transduction pathways in murine embryonic palate mesenchymal cells. 1246 95

Soy isoflavones have been reported to be natural chemopreventive in several types of human cancer. Daidzein and genistein are two main components of soy isoflavones. In our previous study, they were shown to be anti-proliferative and induce cell cycle arrest at S phase of SHZ-88 rat breast cancer cells. We hypothesized that soy isoflavones might exert its anticancer effect by activating cAMP/PKA pathway. The present study was designed to analyze the effect of soy isoflavones on the cAMP/PKA pathway in SHZ-88 cells. Daidzein and genistein were dissolved in DMSO. Cells were treated with 50 mug/ml daidzein and 15 mug/ml genistein, respectively, and with only equal DMSO in the culture medium as control. The cellular cAMP content was tested by radioimmunoassay (RIA). The activity of adenylate cyclase (AC), phosphodiesterase (PDE) and PKA were measured by RIA and (gamma-(32)P) ATP incorporation. Reverse transcript-polymerase chain reaction (RT-PCR) was used to analyze the expression of cAMP response element binding protein (CREB) mRNA of the cells. The results showed that the concentration of cAMP in the cells treated with 50 mug/ml daidzein and 15 mug/ml genistein was significantly increased by 9.5%and 11.0%, respectively, 5 min later (P<0.05), then increased by 31.0%and 40.3%, respectively, 10 min later (P<0.01), compared with that of the control group cells. The activity of AC was not affected during the course of experiment, but that of PDE was decreased to 71.8%and 71.6%, respectively, in the control group 5 min later (P<0.05). The PKA activity was increased to 125.8%and 122.3%, respectively, in the control group 20 min after the cells were treated with daidzein and genistein (P<0.05), and kept at high level till 40 min after treatment. CREB mRNA of the cells treated with daidzein and genistein was increased by 31.6%and 51.1%, respectively, 3 h later (P<0.05), then began to decrease 6 h after treatment. The current study suggests that soy isoflavones activate the cAMP/PKA pathway in SHZ-88 rat breast cancer cells by inhibiting the activity of phosphodiesterase.
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PMID:[Effect of soy isoflavones on cAMP/PKA pathway in breast cancer cells of the rat.]. 1609 2

Multiple intracellular and extracellular regulatory factors affect transcription of the tyrosine hydroxylase (TH) gene encoding the rate-limiting enzyme in the biosynthesis of the neurotransmitters dopamine, norepinephrine and epinephrine. Short chain fatty acids like butyrate are known to alter TH gene expression, but the mechanism of action is unknown. In this report, transient transfection assays identified the proximal TH promoter to contain sufficient genetic information to confer butyrate responsiveness to a reporter gene. Deletion studies and gel shift analyses revealed that the promoter region spanning the cAMP response element is an absolute requirement for transcriptional activation by butyrate. The branched short chain fatty acid valproate is used for seizure control in humans. Significantly, it has a similar aliphatic structure to butyrate, and it was found to have similar effects on TH in PC12 cells. Site-directed mutagenesis indicated that the effects of both fatty acids were mediated through the canonical CRE. Butyrate treatment also resulted in CREB phosphorylation without changing CREB protein levels. The increased phosphorylation of CREB correlated with accumulation of TH mRNA. The adenylate cyclase inhibitor dideoxyadenosine blocked both CREB phosphorylation and accumulation of TH mRNA. The data are consistent with the conclusion that butyrate induces post-translational modifications of pre-existing CREB molecules in a cAMP/PKA-dependent manner to alter TH transcription. These results support the role of butyrate as a novel exogenous regulatory factor in TH gene expression. Our data delineate a molecular mechanism through which diet-derived environmental signals (e.g. butyrate) can modulate catecholaminergic systems by affecting TH gene transcription.
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PMID:Short chain fatty acids regulate tyrosine hydroxylase gene expression through a cAMP-dependent signaling pathway. 1621 87

Butyrate modulates specific gene expression through various second-messenger signal transduction systems including activation of the PKA/cAMP pathway (Decastro, M., Nankova, B.B., Shah, P., Patel, P., Mally, P.V., Mishra, R., La Gamma, E.F., 2005. Short chain fatty acids regulate tyrosine hydroxylase gene expression through a cAMP-dependent signaling pathway, Brain Res. Mol. Brain Res. 142 28-38; Mally, P., Mishra, R., Gandhi, S., Decastro, M.H., Nankova, B.B., Lagamma, E.F., 2004. Stereospecific regulation of tyrosine hydroxylase and proenkephalin genes by short-chain fatty acids in rat PC12 cells, Pediatr. Res. 55 847-854). In the current report, we provide additional evidence that exposure to butyrate causes a rapid activation of the MAP kinase pathway, associated with increased phosphorylation of CREB. Under these conditions, no changes in relative amounts of CREB protein were observed by Western blot. Pre-treatment with the MAPK specific inhibitor (U0126) or the adenylate cyclase inhibitor dideoxyadenosine (ddA) abolished the butyrate-induced: (i) accumulation of TH mRNA, (ii) the phosphorylation of ERK1/2 as well as (iii) CREB phosphorylation. PC12 cells transfected with a TH promoter-luciferase reporter gene showed a robust induction in response to butyrate that was significantly reduced after co-transfection of either of two dominant-negative CREB expression vectors. Nuclear run-on assays demonstrated that butyrate increases endogenous TH gene transcription. We conclude that the initial steps of butyrate-induced gene activation are mediated through the CREB/CREB family of transcription factors which are coupled to both the MAP kinase and cAMP-dependent second messenger systems. Our data delineate a molecular mechanism through which short chain fatty acid's, their related drug-congeners (e.g., valproate) or even diet-derived butyrate (from fermentation of carbohydrates in the gut) can in principle, modulate brain catecholaminergic systems by modifying TH gene expression, dopaminergic levels and the corresponding animal behavior. These molecular relationships also offer a plausible explanation of how the well-recognized clinical effects of ketogenic diets can alter human behavior via the same central mechanisms.
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PMID:Short chain fatty acids induce TH gene expression via ERK-dependent phosphorylation of CREB protein. 1685 87

We have reported previously that interferon-alpha (IFN-alpha) induces apoptosis that is counteracted by an epidermal growth factor (EGF) --> Ras --> extracellular signal-regulated kinase (ERK)-dependent survival response in human epidermoid cancer KB cells. We have studied the effects of the cytokine on the cAMP-dependent pathway in these cells. A decrease in the intracellular cAMP levels was recorded in KB cells treated with IFN-alpha, whereas forskolin induced an increase in the production of cAMP that was reduced in the presence of IFN-alpha, suggesting a reduction in the activity of adenylate cyclase (AC) induced by IFN-alpha. These effects were paralleled by significant change in the expression of some AC catalytic subunit(s) and by reduction in the activity of protein kinase A (PKA). 8-Br-cAMP completely antagonized the reduction of PKA activity induced by IFN-alpha, whereas PKA inhibitor KT5720 enhanced the reduction of the enzyme activity induced by IFN-alpha. We have found that IFN-alpha induced a decrease in cAMP response element binding protein (CREB) phosphorylation without changes in its total expression. The concomitant treatment with IFN-alpha and 8-Br-cAMP potentiated and KT5720 counteracted apoptosis induced by IFN-alpha alone. In conclusion, these data suggest that the decrease in AC/cAMP pathway activity is a survival response to the apoptosis induced by IFN-alpha. Therefore, this pathway could represent a target to enhance the antitumor activity of IFN-alpha.
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PMID:Adenylate cyclase/cAMP pathway downmodulation counteracts apoptosis induced by IFN-alpha in human epidermoid cancer cells. 1731 40


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