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)

We employed a cyclic AMP-resistant subclone of UMR 106-01 osteoblastic osteosarcoma cells (UMR 4-7) with a regulated, dominant-negative mutation of cyclic AMP-dependent protein kinase (PK-A), to examine the mechanism(s) whereby parathyroid hormone (PTH) regulates growth of these cells. Expression of a transiently transfected CAT reporter gene controlled by the cAMP response element of the rat somatostatin gene ('SST-CAT') was used to monitor PK-A activation in intact cells. Agonist-stimulated SST-CAT expression was specific for agents known to activate adenylate cyclase, required an intact cAMP response element and was specifically blocked following induction of the mutant cAMP-resistant phenotype in UMR 4-7 cells. Inhibition of the proliferation of UMR 106-01 cells by PTH, which is mimicked by forskolin and 8-bromo-cAMP, was blocked completely in mutant cyclic AMP-resistant UMR 4-7 cells. We conclude that control of proliferation in UMR 106-01 cells by PTH involves the cAMP messenger system and requires activation of PK-A.
 ...
PMID:Regulation of gene transcription and proliferation by parathyroid hormone is blocked in mutant osteoblastic cells resistant to cyclic AMP. 135 85

The muscle regulatory protein myogenin accumulates in differentiating muscle cells when the culture medium is depleted for serum. To investigate the regulation of myogenin gene expression, we have isolated and characterized the Myf4 gene which encodes the human homologue of murine myogenin. Serum components, basic FGF (b-FGF), transforming growth factor beta (TGF-beta), and EGF, agents which suppress differentiation of muscle cells in vitro, down-regulate the activity of the Myf4 gene, suggesting that it constitutes a nuclear target for the negative control exerted by these factors. The 5' upstream region containing the Myf4 promoter confers activity to a CAT reporter plasmid in C2C12 myotubes but not in fibroblasts and undifferentiated myoblasts. Unidirectional 5' deletions of the promoter sequence reveal that integral of 200 nucleotides upstream of the transcriptional start site are sufficient for cell type-specific expression. The forced expression of the muscle determining factors, MyoD1, Myf5, and Myf6 and to a lesser degree Myf4, results in the transactivation of the Myf4 promoter in C3H mouse 10T1/2 fibroblasts. Pathways potentially involved in conveying signals from the cell-surface receptors to the Myf4 gene were probed with pertussis- and cholera toxin, forskolin, and cAMP. Dibutyryl-cAMP and compounds that stimulate adenylate cyclase inhibit the endogenous Myf4 gene and the Myf4 promoter in CAT and LacZ reporter constructs. Conversely, pertussis toxin which modifies Gi protein stimulates Myf4 gene expression. In summary, our data provide evidence that the muscle-specific expression of the Myf4 gene is subject to negative control by serum components, growth factors and a cAMP-dependent intracellular mechanism. Positive control is exerted by a pertussis toxin-sensitive pathway that presumably involves G proteins.
 ...
PMID:Transcription of the muscle regulatory gene Myf4 is regulated by serum components, peptide growth factors and signaling pathways involving G proteins. 165 74

IL-1, like other agents that have been shown a capacity to induce protein kinase C, is a potent transcriptional activator of the metalloproteinase, stromelysin, in synovial and other fibroblasts. cAMP has been shown to inhibit stromelysin transcription in fibroblasts of nonsynovial origin, and is regarded as an important second messenger for IL-1. In addition to stimulating metalloproteinase transcription, IL-1 also induces PGE2 production in synoviocytes. We determined that rIL-1 alpha led to the time-dependent accumulation of intracellular cAMP in serum-starved rheumatoid synovial fibroblasts, and that the effect was blocked by indomethacin. The cAMP agonists forskolin, 3-isobutyl-1-methylxanthine, and PGE2 suppressed the IL-1 induction of stromelysin; conversely, indomethacin superinduced IL-1-elicited stromelysin mRNA. These results were recapitulated on the transcriptional level in cells transfected with the rat transin/stromelysin promoter in a reporter (CAT) construct. 2',5'-Dideoxyadenosine, an inhibitor of adenylate cyclase, also augmented the IL-1 induction of stromeylsin mRNA, as did H-8, a specific inhibitor of the cAMP-dependent protein kinase A. Staurosporine and H-7, inhibitors of protein kinase C, blocked the IL-1 induction of stromelysin mRNA. We conclude that IL-1 appears to stimulate at least two transduction pathways in synovial fibroblasts from patients with rheumatoid arthritis, and that these have antagonistic effects on the regulation of stromelysin transcription.
 ...
PMID:IL-1 regulation of transin/stromelysin transcription in rheumatoid synovial fibroblasts appears to involve two antagonistic transduction pathways, an inhibitory, prostaglandin-dependent pathway mediated by cAMP, and a stimulatory, protein kinase C-dependent pathway. 217 73

Transcription of proto-oncogene fos is induced by elevated levels of intracellular cAMP. We report that human c-fos promoter recombinants transfected into rat pheochromocytoma cells (PC12) and human choriocarcinoma cells (JEG-3) are induced by stimulation of adenylate cyclase and that this induction is diminished considerably in the mutant PC12 cell line A126-1B2, which is deficient in cAMP-dependent protein kinase II. An element centered at position -60 of the c-fos promoter, which encompasses a consensus cAMP response element (CRE), is sufficient to confer cAMP responsiveness to a herpes thymidine kinase/CAT fusion gene. The specific binding of a nuclear protein to the c-fos CRE can be competed by the somatostatin and alpha-chorionic gonadotropin (alpha-CG) promoter regions that contain CREs. Gel mobility shift assays with double-stranded oligonucleotides containing either the wild-type or mutated c-fos CRE sequence have demonstrated that binding occurs only to the wild-type CRE. The nuclear factor binding to the c-fos CRE is likely to be transcription factor CREB (CRE nuclear binding protein), because an affinity-purified 43-kD CREB isolated from PC12 cells binds efficiently in a DNA footprinting assay. Thus, regulation of the c-fos gene transcription appears to involve a mechanism common to many genes that respond to cAMP as a second message leading to cell growth and differentiation.
 ...
PMID:Induction of proto-oncogene fos transcription through the adenylate cyclase pathway: characterization of a cAMP-responsive element. 285 Sep 67

The specific binding of [125I]hCG to rat testicular membrane preparations was investigated as a function of membrane fluidity changed by lipids. Membrane fluidity was measured either by fluorescence depolarization of diphenylhexatriene or ESR spectra of I(1,14), I(12,3) and CAT 16 incorporated into the membrane. Incubation of membrane with cholesteryl-hemisuccinate increased both the rigidity of membrane lipids and the specific binding of [125I]hCG. A similar rigidifying action of saturated fatty acids was, however, not accompanied by increased accessibility of LH/hCG receptors. Treatment of testicular membranes with unsaturated fatty acids enhanced membrane fluidity but specific binding of the gonadotropin disappeared. In spite of the increase of LH/hCG receptors in cell membranes treated with cholesteryl-hemisuccinate, Leydig cells showed decreased sensitivity to cAMP response to LH stimulation. The results indicate that newly exposed LH/hCG receptors are not coupled with the adenylate cyclase system.
 ...
PMID:Modulation of rat testicular LH/hCG receptors by membrane lipid fluidity. 300 83

Prostanoids induce expression of several immediate-early genes, but the molecular mechanisms underlying these responses remain poorly characterized. We studied induction of the proto-oncogene c-fos by PGE2 in mesangial cells as a model of gene regulation by prostanoids. PGE2 induced marked and transient accumulation of c-fos mRNA. Addition of exogenous 8-bromo-cAMP or forskolin failed to induce c-fos mRNA, suggesting that activation of an EP2 receptor linked to adenylate cyclase did not account for induction of c-fos by PGE2. These data contrast with previous experiments in NIH 3T3 cells in which PGE2 induced c-fos by a cAMP-dependent mechanism. Depletion of protein kinase C blocked induction of c-fos mRNA by PGE2, whereas a protein tyrosine kinase inhibitor had no effect. We further showed that PGE2 induces the c-fos gene by increasing the transactivating capacity of the serum-response element. Transient transfections with a CAT fusion gene driven by an AP-1 cis-element demonstrated that although PGE2 markedly induced c-fos, PGE2 did not increase AP-1-driven transcriptional responses. Electrophoretic gel mobility shift assays revealed that PGE2 failed to increase binding of AP-1 complexes to a consensus AP-1 DNA sequence. Taken together, these experiments provide evidence for a cAMP-independent, protein kinase C-dependent pathway linking a PGE2 receptor on the plasma membrane to transcriptional activation in the nucleus. Regulation of gene transcription by PGE2 probably involves c-fos induction without concomitant activation of AP-1.
 ...
PMID:PGE2 induces c-fos expression by a cAMP-independent mechanism in glomerular mesangial cells. 752 23

Basic fibroblast growth factor (FGF-2) is synthesized as different molecular mass isoforms all lacking the signal-peptide sequence. The high molecular-mass isoforms (21-24 kDa) possess a signal sequence directing their nuclear translocation. The role of each isoform is still poorly understood, however, modifications in intracellular signalling pathways could explain some effects of these peptides. In order to evaluate the role of FGF-2 isoforms on the adenylate cyclase (AC) signalling pathway, we retrovirally infected a rat pancreatic cell line (AR4-2J) with point-mutated FGF-2 cDNAs, allowing the expression of the 18 (A5 cells) or 22.5 kDa isoform (A3 cells) at a low level. In membrane preparations of A3 cells, unscheduled expression of the 22.5 kDa FGF-2 isoform induced a 2-fold decrease in both basal and forskolin-stimulated AC activity. Studies carried out on intact cells also showed decreased accumulation of cAMP in A3 cells in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. Both FGF-2 peptides also induced functional modifications of G-proteins without affecting their levels. The 22.5 kDa peptide led to enhanced ADP-ribosylation of both alpha(s)-subunits in vitro, whereas the expression of the low molecular-mass 18 kDa peptide resulted in a 2-fold increase in alpha12 and alpha0 ADP-ribosylations. Furthermore, control CAT cells (AR4-2J cells transfected with the retrovirus containing the chloramphenicol acetyltransferase gene) and A5 cells were growth-inhibited by 8-Br-cAMP, in contrast to A3 cells. These data provide evidence that the expression of FGF-2 peptides could play a role in cell functions by modifying the AC signalling pathway. FGF-2 peptides are able to modulate both AC activity and the regulatory G-proteins. Finally FGF-2 expression may interfere with cAMP-regulated cell proliferation.
 ...
PMID:Cells retrovirally transfected with fibroblast growth factor-2 isoforms exhibit altered adenylate cyclase activity and G-protein functionality. 861 38

A number of candidate Egr-1 neuronal target genes have been identified including the synapsin I gene. Previous studies have shown that over-expression of Egr-1 in cells transfected with an Egr-1 expression vector is sufficient to activate reporter genes linked to regions of the synapsin I promoter, but any effect on the expression of synapsin I within its genomic context has not been demonstrated. We tested our hypothesis that modulation of synapsin I expression by Egr-1 requires the presence of elevated cAMP which would normally be present during periods of neuronal plasticity. Both the adenyl cyclase activator, forskolin (frsk), and the cAMP analogue, Sp-Adenosine 3',5'-cyclic monophosphorothioate triethylammonium salt (Sp-cAMPS), enhanced the ability of Egr-1 to transactivate a CAT reporter plasmid containing multiple copies of the Egr-1 binding site (EBS). Furthermore, Egr-1 alone had minimal effects on synapsin I expression whereas forskolin treatment of PC12 cells profoundly affected the ability of Egr-1 to regulate synapsin I expression. These results suggest that Egr-1 transactivation during neuronal plasticity may rely on a permissive effect of cAMP.
 ...
PMID:Egr-1 modulation of synapsin I expression: permissive effect of forskolin via cAMP. 1538 Dec 51