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)

Macrophage migration-inhibitory factor (MIF) has recently been identified as a pituitary hormone that functions as a counterregulatory modulator of glucocorticoid action within the immune system. In the anterior pituitary gland, MIF is expressed in TSH- and ACTH-producing cells, and its secretion is induced by CRF. To investigate MIF function and regulation within pituitary cells, we initiated the characterization of the MIF 5'-regulatory region of the gene. The -1033 to +63 bp of the murine MIF promoter was cloned 5' to a luciferase reporter gene and transiently transfected into freshly isolated rat anterior pituitary cells. This construct drove high basal transcriptional activity that was further enhanced after stimulation with CRF or with an activator of adenylate cyclase. These transcriptional effects were associated with a concomitant rise in ACTH secretion in the transfected cells and by an increase in MIF gene expression as assessed by Northern blot analysis. A cAMP-responsive element (CRE) was identified within the MIF promoter region which, once mutated, abolished the cAMP responsiveness of the gene. Using this newly identified CRE, DNA-binding activity was detected by gel retardation assay in nuclear extracts prepared from isolated anterior pituitary cells and AtT-20 corticotrope tumor cells. Supershift experiments using antibodies against the CRE-binding protein CREB, together with competition assays and the use of recombinant CREB, allowed the detection of CREB-binding activity with the identified MIF CRE. These data demonstrate that CREB is the mediator of the CRF-induced MIF gene transcription in pituitary cells through an identified CRE in the proximal region of the MIF promoter.
 ...
PMID:Transcriptional activation of the macrophage migration-inhibitory factor gene by the corticotropin-releasing factor is mediated by the cyclic adenosine 3',5'- monophosphate responsive element-binding protein CREB in pituitary cells. 960 32

The observation that human herpesvirus 6 (HHV-6) can induce CD4 gene transcription and expression in CD4(-) cells was reported several years ago (P. Lusso, A. De Maria, M. Malnati, F. Lori, S. E. DeRocco, M. Baseler, and R. C. Gallo, Nature 349:533-535, 1991) and subsequently confirmed (P. Lusso, M. S. Malnati, A. Garzino-Demo, R. W. Crowley, E. O. Long, and R. C. Gallo, Nature 362:458-462, 1993; G. Furlini, M. Vignoli, E. Ramazzotti, M. C. Re, G. Visani, and M. LaPlaca, Blood 87:4737-4745, 1996). Our objective was to identify the mechanisms underlying such phenomena. Using reporter gene constructs driven by the CD4 promoter, we report that HHV-6 can efficiently transactivate such genetic elements. Activation of the CD4 promoter occurs in the presence of the viral DNA polymerase inhibitor phosphonoformic acid, which limits expression to the immediate-early and early classes of viral genes. Using deletion mutants and specific CD4 promoter mutants, we identified an ATF/CRE binding site located at nucleotides -67 to -60 upstream of the CD4 gene transcription start site that is important for HHV-6 transactivation. The ATF/CRE site is also essential for CD4 promoter activation by forskolin, an activator of adenylate cyclase. Using electrophoretic mobility shift assays and specific antibodies, we showed that CREB-1 binds specifically to the -79 to -52 region of the CD4 promoter. Last, we have identified two open reading frames (ORFs) of HHV-6, U86 and U89 from the immediate-early locus A, that can transactivate the CD4 promoter in HeLa cells. However, transactivation of the CD4 promoter by ORFs U86 and U89 is independent of the CRE element, suggesting that additional HHV-6 ORFs are likely to contribute to CD4 gene activation. Taken together, our results will help to understand the complex interactions occurring between HHV-6 and the CD4 promoter and provide additional information regarding the class of transcription factors involved in the control of CD4 gene expression.
 ...
PMID:CD4 promoter transactivation by human herpesvirus 6. 976 24

Tumor necrosis factor alpha (TNFalpha), an early cytokine produced by activated macrophages, plays an essential role in normal and pathological inflammatory reactions. The excessive production of TNFalpha is prevented by the so-called "macrophage-deactivating factors." This study examines the role of two structurally related neuropeptides, the vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating peptide (PACAP), as inhibitors of TNFalpha. Both VIP and PACAP inhibit TNFalpha production from lipopolysaccharide-stimulated RAW 246.7 cells in a dose- and time-dependent manner. Although the activated cells express mRNA for all three VIP/PACAP receptors, agonist and antagonist studies indicate that the major receptor involved is VIP1R. VIP/PACAP inhibit TNFalpha gene expression by affecting both NF-kB binding and the composition of the cAMP responsive element binding complex (CREB/c-Jun). Two transduction pathways, a cAMP-dependent and a cAMP-independent pathway, are involved in the inhibition of TNFalpha gene expression and appear to differentially regulate the transcriptional factors involved. Because TNFalpha plays a central role in various inflammatory diseases such as endotoxic shock, multiple sclerosis, cerebral malaria, and various autoimmune conditions, the down-regulatory effect of VIP/PACAP may have a significant therapeutic potential.
 ...
PMID:Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit tumor necrosis factor alpha transcriptional activation by regulating nuclear factor-kB and cAMP response element-binding protein/c-Jun. 981 54

In recent years there have been remarkable developments toward the understanding of the molecular and/or cellular changes in the neuronal second-messenger pathways during ethanol dependence. In general, it is believed that the cyclic adenosine 3',5'-monophosphate (cAMP) and the phosphoinositide (PI) signal-transduction pathways may be the intracellular targets that mediate the action of ethanol and ultimately contribute to the molecular events involved in the development of ethanol tolerance and dependence. Several laboratories have demonstrated that acute ethanol exposure increases, whereas protracted ethanol exposure decreases, agonist-stimulated adenylate cyclase activity in a variety of cell systems, including the rodent brain. Recent studies indicate that various postreceptor events of the cAMP signal transduction cascade (i.e., Gs protein, protein kinase A [PKA], and cAMP-responsive element binding protein [CREB]) in the rodent brain are also modulated by chronic ethanol exposure. The PI signal-transduction cascade represents another important second-messenger system that is modulated by both acute and chronic ethanol exposure in a variety of cell systems. It has been shown that protracted ethanol exposure significantly decreases phospholipase C (PLC) activity in the cerebral cortex of mice and rats. The decreased PLC activity during chronic ethanol exposure may be caused by a decrease in the protein levels of the PLC-beta 1 isozyme but not of PLC-delta 1 or PLC-gamma 1 isozymes in the rat cerebral cortex. Protein kinase C (PKC), which is a key step in the PI-signaling cascade, has been shown to be altered in a variety of cell systems by acute or chronic ethanol exposure. It appears from the literature that PKC plays an important role in the modulation of the function of various neurotransmitter receptors (e.g., gamma-aminobutyrate type A [GABAA], N-methyl-D-aspartate [NMDA], serotonin2A [5-HT2A], and 5-HT2C, and muscarinic [m1] receptors) resulting from ethanol exposure. The findings described in this review article indicate that neuronal-signaling proteins represent a molecular locus for the action of ethanol and are possibly involved in the neuro-adaptational mechanisms to protracted ethanol exposure. These findings support the notion that alterations in the cAMP and the PI-signaling cascades during chronic ethanol exposure could be the critical molecular events associated with the development of ethanol dependence.
 ...
PMID:Neuronal signaling systems and ethanol dependence. 988 43

The cAMP signalling pathway plays a key role in the regulation of the hypothalamic-pituitary-adrenal axis. Transcription factor CREM (cAMP response element modulator) is implicated in the modulation of a number of neuroendocrine functions. By virtue of an alternative, intronic promoter CREM generates the powerful transcriptional repressor ICER (inducible cAMP early repressor), which displays a pronounced neuroendocrine-specific expression. Here we document a remarkable induction of ICER in response to acute stress in the intermediate lobe (IL) of the pituitary gland. The induction is transient and is preceded by CREB phosphorylation. Adrenergic stimulation directs ICER induction in the IL through the activation of both beta2-adrenergic and corticotrophin-releasing hormone receptors. These receptors are positively coupled to the adenylate cyclase signalling pathway, which regulates hormone release from the IL, implicating ICER in the modulation of peptide secretion. We show that targeted ablation of the CREM gene in the mouse causes a chronic increase of beta-endorphin levels. Altered hormonal production occurs both in basal conditions and after stress. Thus, early ICER induction in the IL may be involved in the modulation of gene expression in response to stress.
 ...
PMID:The inducible cyclic adenosine monophosphate early repressor (ICER) in the pituitary intermediate lobe: role in the stress response. 1058 Aug 43

In eukaryotes, transcriptional regulation on stimulation of the adenylate cyclase signaling pathway is mediated by a family of cyclic AMP-responsive nuclear factors, including CREB, CREM, and ATF-1. These factors contain the basic domain/leucine zipper motifs and bind as dimers to cAMP-responsive elements (CREs). The activation function of CRE-binding proteins is modulated by phosphorylation by several kinases and is mediated by coactivators such as CBP and p300. Activation might also be independent of CBP and phosphorylation in some specific cell types, such as male germ cells, wherein the protein ACT confers a powerful activation function to CREM. The inducible cAMP early repressor (ICER) protein is the only inducible member of this family. The induction of this powerful repressor is likely to be important for the transient nature of cAMP-induced gene expression. CRE-binding proteins have been found to play an important role in the physiology of the pituitary gland, in regulating spermatogenesis, in the response to circadian rhythms, and in the molecular basis of memory.
 ...
PMID:Transcriptional regulation by cyclic AMP-responsive factors. 1069 14

Glucagon-like peptide 1 (GLP-1), a hormonal activator of adenyl cyclase, stimulates insulin gene transcription, an effect mediated by the cAMP response element (CRE) of the rat insulin I gene promoter (RIP1). Here we demonstrate that the signaling mechanism underlying stimulatory effects of GLP-1 on insulin gene transcription results from protein kinase A (PKA)-independent activation of the RIP1 CRE. Although GLP-1 stimulates cAMP production in rat INS-1 insulinoma cells, we find accompanying activation of a -410-bp RIP1 luciferase construct (-410RIP1-LUC) to exist independently of this second messenger. GLP-1 produced a dose-dependent stimulation of -410RIP1-LUC (EC50 0.43 nmol/l), an effect reproduced by the GLP-1 receptor agonist exendin-4 and abolished by the antagonist exendin(9-39). Activation of RIP1 by GLP-1 was not affected by cotransfection with dominant-negative Gs alpha, was not blocked by cAMP antagonist Rp-cAMPS, and was insensitive to PKA antagonist H-89. Truncation of -410RIP1-LUC to generate -307-, -206-, and -166-bp constructs revealed 2 segments of RIP1 targeted by GLP-1. The first segment, not regulated by forskolin, was located between -410 and -307 bp of the promoter. The second segment, regulated by both GLP-1 and forskolin, included the CRE and was located between -206 and -166 bp. Consistent with these observations, stimulatory effects of GLP-1 at RIP1 were reduced after introduction of delta-182 and delta-183/180 inactivating deletions at the CRE. The action of GLP-1 at -410RIP1-LUC was also reduced by cotransfection with A-CREB, a genetically engineered isoform of the CRE binding protein CREB, which dimerizes with and prevents binding of basic-region-leucine-zipper (bZIP) transcription factors to the CRE. In contrast, the action of GLP-1 at the CRE was not blocked by cotransfection with M1-CREB, an isoform that lacks a consensus serine residue serving as substrate for PKA-mediated phosphorylation. On the basis of these studies, it is proposed that PKA-independent stimulatory actions of GLP-1 at RIP1 are mediated by bZIP transcription factors related in structure but not identical to CREB.
 ...
PMID:Glucagon-like peptide 1 stimulates insulin gene promoter activity by protein kinase A-independent activation of the rat insulin I gene cAMP response element. 1090 73

Transient transfection of mouse gonadotrope-derived (alphaT3-1) cells with a 2297 bp human GnRHR promoter-luciferase construct (p2300-LucF) showed a dose- and time-dependent increase in the human gonodotropin-releasing hormone receptor (GnRHR) promoter activity after forskolin treatment. An average of 4.8-fold increase in promoter activity was observed after 12 h of 10 microM forskolin treatment. This effect was mimicked by administration of cholera toxin, cAMP analog or pituitary adenylate cyclase activating polypeptide 38 (PACAP). A specific adenylate cyclase (AC) inhibitor (ACI) or protein kinase A (PKA) inhibitor (PKAI) pretreatment reversed the forskolin- and PACAP-induced increase in the human GnRHR promoter activity. These results not only confirm the stimulatory effect of Cyclic adenosine monophosphate (cAMP) in human GnRHR promoter activation, but also suggest that hormones or neurotransmitters that activate adenylate cyclase in pituitary gonadotropes may increase the expression of human GnRHR gene in transcriptional level. Progressive 5' deletion assays identified a 412 bp fragment (-577 to 167) in the human GnRHR 5'-flanking region that is essential in maintaining the basal responsiveness to cAMP. Mutagenesis coupled with functional studies have identified two putative AP-1/CREB binding sites, namely hGR-AP/CRE-1 and hGR-AP/CRE-2 that participated in mediating the cAMP-stimulatory effect. Mutation of the putative hGR-AP/CRE-1 and hGR-CRE-2 resulted in a 38 and 32% decrease in the forskolin-induced stimulation. However, mutation of both binding sites did not completely abolish the cAMP-stimulatory effect, suggesting that multiple transcription factor binding sites were involved in full response in cAMP stimulation. The binding of CREB to these motifs was confirmed by gel mobility shift assay and antibody supershift assay.
 ...
PMID:Human gonadotropin-releasing hormone receptor gene transcription: up-regulation by 3',5'-cyclic adenosine monophosphate/protein kinase A pathway. 1147 37

Chronic administration of noradrenergic antidepressants causes a desensitization of the beta adrenoceptor coupled adenylate cyclase system. In the present studies, we attempted to answer the question of whether or not this deamplification is reflected beyond the second messenger system. Nuclear CREB-P was determined in frontal cortex of rats following acute and chronic administration of desipramine (DMI) or reboxetine and in human fibroblasts following incubation for 48 hours with DMI, reboxetine or venlafaxine. Nuclear CREB-P in the frontal cortex was significantly decreased following chronic administration of DMI or reboxetine. Moreover, incubation of human fibroblasts with DMI or reboxetine, but not with venlafaxine, caused a highly significant reduction in nuclear CREB-P suggesting that the noradrenergic antidepressants exert direct effects beyond beta adrenoceptors. The results are consistent with the view that chronic treatment with antidepressants causes a net deamplification of the norepinephrine mediated signal transduction cascade which might "normalize" the increased noradrenergic activity evident in major depression.
 ...
PMID:Noradrenergic antidepressants: does chronic treatment increase or decrease nuclear CREB-P? 1179 65

The myocardial beta-adrenergic receptor (betaAR) system plays a key role in dysfunctional signaling and physiology of the failing heart. Recently we described a murine model of dilated cardiomyopathy (DCM) produced by cardiac-specific expression of a dominant negative form of the CREB transcription factor (CREB(A133) mice). CREB(A133) mice display abnormalities within the betaAR signaling system including loss of inotropic reserve. Rapid desensitization of betaARs is mediated by the betaAR kinase (betaARK1), which is upregulated during heart failure. Inhibition of betaARK1 activity in the heart via expression of a peptide inhibitor (betaARKct) has been shown to enhance myocardial function and to "rescue" several animal models of heart failure. To determine the role of betaAR dysfunction in the progression of DCM in the CREB(A133) mice, we interbred them with mice expressing the betaARKct. Concurrent expression of the betaARKct peptide and CREB(A133) in mouse hearts resulted in the normalization of elevated betaARK1 levels. This biochemical change resulted in partial restoration of isoproterenol-stimulated adenylate cyclase activity as well as improvement in fractional shortening in response to betaAR stimulation. Interestingly, the progression of DCM and premature mortality was not altered. Therefore, the pathogenesis of DCM in CREB(A133) mice does not appear to involve abnormal betaAR signaling as a key element in its pathological progression and accordingly, the restoration of betaAR signaling is not sufficient to prevent the development and progression of all forms of heart failure.
 ...
PMID:Inhibition of betaARK1 restores impaired biochemical beta-adrenergic receptor responsiveness but does not rescue CREB(A133) induced cardiomyopathy. 1205 54


<< Previous 1 2 3 4 5 6 7 8 Next >>