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)

The stimulation of gastric acid secretion from parietal cells involves both intracellular calcium and cAMP signaling. To understand the effect of increased cAMP on parietal cell function, we engineered transgenic mice expressing cholera toxin (Ctox), an irreversible stimulator of adenylate cyclase. The parietal cell-specific H(+),K(+)-ATPase beta-subunit promoter was used to drive expression of the cholera toxin A1 subunit (CtoxA1). Transgenic lines were established and tested for Ctox expression, acid content, plasma gastrin, tissue morphology, and cellular composition of the gastric mucosa. Four lines were generated, with Ctox-7 expressing approximately 50-fold higher Ctox than the other lines. Enhanced cAMP signaling in parietal cells was confirmed by observation of hyperphosphorylation of the protein kinase A-regulated proteins LASP-1 and CREB. Basal acid content was elevated and circulating gastrin was reduced in Ctox transgenic lines. Analysis of gastric morphology revealed a progressive cellular transformation in Ctox-7. Expanded patches of mucous neck cells were observed as early as 3 mo of age, and by 15 mo, extensive mucous cell metaplasia was observed in parallel with almost complete loss of parietal and chief cells. Detection of anti-parietal cell antibodies, inflammatory cell infiltrates, and increased expression of the Th1 cytokine IFN-gamma in Ctox-7 mice suggested that autoimmune destruction of the tissue caused atrophic gastritis. Thus constitutively high parietal cell cAMP results in high acid secretion and a compensatory reduction in circulating gastrin. High Ctox in parietal cells can also induce progressive changes in the cellular architecture of the gastric glands, corresponding to the development of anti-parietal cell antibodies and autoimmune gastritis.
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PMID:Parietal cell hyperstimulation and autoimmune gastritis in cholera toxin transgenic mice. 1639 75

Failure in obtaining expression of functional adrenocorticotropic hormone receptor (ACTHR, or melanocortin 2 receptor, MC2R) in non-adrenal cells has hindered molecular analysis of ACTH signaling pathways. Here, we ectopically expressed the mouse ACTHR in Balb/c mouse 3T3 fibroblasts to analyze ACTH signaling pathways involved in induction of fos and jun genes. Natural constitutive expression of the MC2R accessory protein (MRAP) in Balb3T3 and other mouse 3T3 fibroblasts (NIH, Swiss and 3T3-L1) renders these fibroblastic lines suitable for ectopic expression of ACTHR in its active form properly inserted into the plasma membrane at levels similar to those found in mouse Y1 adrenocortical tumor cells. The Y1 cell line is a cultured cell system well known for stably displaying normal adrenal specific metabolic pathways, ACTHR expression and ACTH functional responses. Thirty-nine sub-lines expressing ACTHR (3T3-AR transfectants) were selected for geneticin-resistance and clonally isolated after transfection of ACTHR-cDNA (in the pSVK3 mammalian plasmidial vector) into Balb3T3 fibroblasts. In addition, sixteen clonal sub-lines of Balb3T3 (3T3-0 transfectants) carrying the pSVK3 empty vector were likewise isolated. Fourteen 3T3-AR and four 3T3-0 clones were screened for response to ACTH(39) in comparison with Y1 adrenocortical cells. Eight 3T3-AR clones responded to ACTH(39) with activation of adenylate cyclase and induction of c-Fos protein, but the levels of, respectively, activation and induction were not strictly correlated. Other fos and jun genes were also induced by ACTH(39) in 3T3-AR transfectants, which express levels of ACTHR protein similar to parental Y1 cells. Signaling pathways relevant to c-Fos induction was extensively investigated in 3 clones: 3T3-AR01 and -07 and 3T3-04. In Y1 cells, specific inhibitors (H89/PKA; PD98059/MEK; Go6983/PKC and SP600125/JNK) show that signals initiated in the ACTH/ACTHR-system activate 4 pathways to induce the c-fos gene, namely: (a) cAMP/PKA/CREB; (b) MEK/ERK1/2; (c) PKC and d) JNK1/2. In 3T3-AR transfectants, both inhibitors PD98059 and Go6983 proved completely ineffective to inhibit c-Fos induction by ACTH(39), implying that MEK/ERK and PKC pathways are not involved in this process. On the other hand, SP600125 caused 85% inhibition of c-Fos induction by ACTH(39) and, in addition, ACTH(39) promotes JNK1/2 phosphorylation, suggesting that JNK is a major signaling pathway mediating c-Fos induction by ACTH(39) in these cells. In addiction, PKA inhibitor H89 also inhibits c-Fos induction in 3T3-AR7 cells by ACTH(39), implicating activation of the cAMP/PKA/CREB pathway in c-Fos induction by ACTH(39). However, the cAMP derivatives db-cAMP and 8Br-cAMP, do not promote CREB phosphorylation and c-Fos induction in parental Balb3T3 and 3T3-AR transfectants, confirming previous report by others. In conclusion, expression of active ACTHR in Balb3T3 fibroblasts renders these cells responsive to ACTH with activation of cAMP/PKA/CREB and JNK pathways and, also, induction of genes from the fos and jun families. These results show that Balb 3T3-AR sublines are useful cellular systems for genetic analysis of ACTH-signaling pathways. However, activation of cAMP/PKA/CREB and JNK pathways and induction of fos and jun genes are not yet sufficient to enable ACTH for interference in morphology, migration and proliferation of Balb3T3 fibroblasts as it does in Y1 adrenocortical cells.
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PMID:ACTH receptor: ectopic expression, activity and signaling. 1684 90

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

Increases in cyclic adenosine monophosphate (cAMP) are proposed to initiate learning in a wide variety of species. Here, we measure changes in cAMP in the olfactory bulb prior to, during, and following a classically conditioned odor preference trial in rat pups. Measurements were taken up to the point of maximal CREB phosphorylation in olfactory bulb mitral cells. Using both drug and natural unconditioned stimuli we found effective learning was associated with an increase in cAMP at the end of the conditioning trial, followed by a decrease 5 min later. This early timing of a transient cAMP increase occurred only when the odor was paired with an effective drug or natural unconditioned stimulus (US). The data support the hypothesis that the rate of adenylate cyclase activation is enhanced by pairing calcium and G-protein activation and that the timing of transient cAMP signaling is critical to the initiation of classical conditioning.
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PMID:A temporal-specific and transient cAMP increase characterizes odorant classical conditioning. 1733 3

Prostaglandins are potent products of arachidonic acid metabolism that play significant roles in regulating ion transport in the kidney. In the Madin Darby canine kidney (MDCK) cell line prostaglandin E(1) (PGE(1)) stimulates the activity of the Na,K-ATPase and regulates transcription. Transient transfection studies conducted in MDCK cells with a human Na,K-ATPase beta1 subunit promoter/luciferase construct, pHbeta1-1141 Luc, showed a PGE(1) stimulation. The PGE(1) stimulation was inhibited by the PGE receptor antagonists SC19220 and AH6809, indicating the involvement of EP1 receptors (coupled to phospholipase C) and EP2 receptors (coupled to adenylate cyclase), respectively. A prostaglandin-regulatory element (PGRE) within the beta1 subunit promoter (-110 to -92, AGTCCCTGC) is sufficient to elicit a PGE(1) stimulation in a heterologous promoter (in pLUC-MCS). Studies with promoter mutants indicated that in addition to the PGRE, an adjacent Sp1 site was also essential for regulation by PGE(1). Consistent with the involvement of Sp1 are the results of DNA affinity precipitation studies, which indicate that Sp1 as well as CREB, and Sp3 all bind to the PGRE. The involvement of this PGRE in transcriptional regulation of the Na,K-ATPase beta1 gene was examined in a number of species. Only human and chimpanzee promoters possessed an identical PGRE site, unlike dog, rat, and mouse, which possessed Sp1 sites in similar locations. Two alternative PGREs were subsequently identified. The sequence of the one of these PGREs (TGACCTTC, -445 to -438) was conserved throughout all species examined, suggesting its physiologic significance.
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PMID:Prostaglandins regulate transcription by means of prostaglandin response elements located in the promoters of mammalian Na,K-ATPase beta 1 subunit genes. 1734 18

Hypothalamic hormones, including dopamine, regulate critical functions of pituitary cells via the cAMP-protein kinase A (PKA) pathway. The PKA-downstream transcription factor cAMP response element (CRE)-binding protein (CREB) is an integrating molecule that is also activated by many other protein kinase pathways. We investigated the involvement of CREB in the regulation of cell proliferation and the PRL promoter of rat lactotrophs in primary cell culture. Recombinant adenoviruses were used for efficient gene delivery into pituitary cells. Bromocriptine, a dopaminergic agonist known to decrease intracellular cAMP concentrations, caused inhibition of PRL promoter activity and lactotroph proliferation, which was accompanied by decreases in CRE-mediated transcription and CREB phosphorylation in lactotrophs. Expression of a dominant-negative form of CREB (MCREB), which was effective in suppressing CRE-mediated transcription induced by the adenylate cyclase activator forskolin, inhibited basal and forskolin-induced PRL promoter activity and PRL mRNA expression. MCREB expression lowered basal proliferative levels and blocked forskolin-induced proliferation of lactotrophs. Insulin-like growth factor I (IGF-I), a potent mitogen in lactotrophs, did not affect intracellular cAMP concentrations but transiently increased lactotroph CREB phosphorylation. MCREB expression also inhibited IGF-I-induced lactotroph proliferation. These results suggest that CREB is involved in the regulation of cell proliferation and the PRL promoter in normal lactotrophs and that dopamine inhibition of these lactotroph functions is at least in part due to inhibition of the cAMP-PKA-CREB pathway.
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PMID:Involvement of cAMP response element-binding protein in the regulation of cell proliferation and the prolactin promoter of lactotrophs in primary culture. 1792 56

Bordetella pertussis causes a profound inflammatory response in lungs of infected individuals. The adenylate cyclase toxin (ACT) of B. pertussis is a potent enzyme that converts cytosolic ATP into cAMP, and is required for virulence in vivo. During infection, secreted ACT binds to macrophages utilizing the beta2 integrin, Mac-1 (CR3, CD11b/CD18), and subsequent intoxication by ACT inhibits essential antibacterial activities of macrophages. Additionally, Mac-1 has been reported to be a co-receptor for TLR4 required for the full induction of some LPS-responsive genes, including pro-inflammatory cyclooxygenase 2 (COX-2). We have examined the effect of ACT on COX-2 expression in HEK293T cells expressing Mac-1 and in murine macrophages. We report that ACT induces COX-2 in a manner that absolutely requires the catalytic activity of this enzyme and Mac-1 expression dramatically enhanced the sensitivity of cells to ACT-dependent COX-2 induction. The mechanism of COX-2 induction by ACT utilizes the cAMP-PKA-CREB-dependent pathway. Finally, ACT and TLR2 or TLR4 act synergistically to increase COX-2 expression. These data suggest that ACT contributes significantly to the inflammatory response induced by B. pertussis infection by augmenting COX-2 expression and provides evidence against the concept that ACT functions exclusively via its inhibitory effects on phagocytic leucocytes.
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PMID:Bordetella pertussis adenylate cyclase toxin (ACT) induces cyclooxygenase-2 (COX-2) in murine macrophages and is facilitated by ACT interaction with CD11b/CD18 (Mac-1). 1792 97

The molecular mechanism of action of the mood stabilizer lithium is assumed to involve changes in gene expression leading to neuronal adaptation. The transcription factor CREB (cAMP-responsive element binding protein) regulates the expression of many genes and has been implicated in important brain functions and the action of psychogenic agents. We here investigated the effect of lithium on cAMP-responsive element (CRE)/CREB-mediated gene transcription in the brain, using transgenic reporter mice that express the luciferase reporter gene under the control of four copies of the rat somatostatin gene promoter CRE. Chronic (21 days) but not acute (24 h) treatment with lithium (7.5 mmol/kg) significantly decreased CRE/CREB-directed gene expression in hippocampus, cortex, hypothalamus, and striatum to 60-70%, and likewise reduced CREB phosphorylation. As bipolar disorder is also considered as a stress-related disorder, the effect of lithium was determined in mice submitted to a paradigm for chronic psychosocial stress. As shown before, stress for 25 days significantly increased CRE/CREB-directed gene expression in several brain regions by 100-150%. Treatment of stressed mice with lithium decreased stress-induced CRE/CREB-directed gene expression to control levels in nearly all brain regions and likewise reduced CREB phosphorylation. Chronic lithium treatment induced beta-catenin accumulation and decreased cAMP levels, indicating an inhibitory effect of lithium on glycogen synthase kinase 3 and the adenylate cyclase/protein kinase A signalling cascade, which are known to modulate CREB activity. We here for the first time show that lithium regulates CRE/CREB-directed gene transcription in vivo and suggest CREB as a putative mediator of the neuronal adaptation after chronic lithium treatment.
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PMID:Chronic lithium salt treatment reduces CRE/CREB-directed gene transcription and reverses its upregulation by chronic psychosocial stress in transgenic reporter gene mice. 1804 4

Neuropeptides, including pituitary adenylate cyclase-activating polypeptide (PACAP), can influence diverse cellular processes over a broad temporal range. In ciliary ganglion (CG) neurons, for example, PACAP binding to high-affinity PAC1 receptors triggers transduction cascades that both rapidly modulate nicotinic receptors and synapses and support long-term survival. Since PACAP/PAC1 signaling recruits intracellular messengers and effectors that potently alter transcription, we examined its activation of the transcription factor CREB and then tested for changes in gene expression. PACAP/PAC1 signaling rapidly induced prolonged CREB activation in CG neurons by a phospholipase C -independent mechanism supported by Ca2+-influx, adenylate cyclase, and effectors, including protein kinase C (PKC) and possibly PKA. Since PACAP is abundant in the CG and released from depolarized presynaptic terminals, it is well suited to regulate gene expression relevant to neuronal and synaptic development. Gene array screens conducted using RNA from CG cultures grown with PACAP for 1/4, 24, or 96 h revealed a time-dependent pattern of > 600 regulated transcripts, including several encoding proteins implicated in synaptic function, neuronal survival, and development. The results underscore rapid, neuromodulatory, and long-term, neurotrophic consequences of PAC1 signaling in CG neurons and suggest that PACAP exerts such diverse influences by altering the expression of specific gene transcripts in a time-dependent fashion.
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PMID:Pituitary adenylate cyclase-activating polypeptide (PACAP) alters parasympathetic neuron gene expression in a time-dependent fashion. 1859 77

Our previous work has shown that lymphocytes synthesize catecholamines (CAs) and the endogenous CAs accelerate apoptosis of concanavalin A (Con A)-activated lymphocyte. Here, we explored the involvement of adrenoreceptors (ARs) and signal molecules coupled to the ARs in the endogenous CA-mediated modulation of lymphocyte apoptosis. Pargyline, an inhibitor of CA degradation, up-regulated the expression of cleaved caspase-3 protein and increased the number of apoptotic cells. Antagonists of alpha(1)-ARs and beta(2)-ARs, not antagonists of alpha(2)-ARs or beta(1)-ARs, blocked these effects of pargyline. The facilitating effects of pargyline on lymphocyte apoptosis were mimicked by activators of adenylate cyclase and PKC, but reversed by inhibitors of PKA, PLC and PKC. Pargyline-stimulated CREB activation and Smac/DIABLO expression were prevented by the inhibitors of PKA, PLC and PKC. These results imply that endogenous CA-induced lymphocyte apoptosis is mediated by cAMP-PKA- and PLC-PKC-linked CREB-Smac/DIABLO pathways coupled with alpha(1)-ARs and beta(2)-ARs.
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PMID:Adrenoreceptor-coupled signal-transduction mechanisms mediating lymphocyte apoptosis induced by endogenous catecholamines. 1955 89


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