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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Destruction of the substantia nigra produces striatal D1 dopamine receptor supersensitivity without increasing receptor number or affinity, thus implicating postreceptor mechanisms. The nature of these mechanisms is unknown. Increased striatal c-fos expression ipsilateral to a unilateral lesion of the substantia nigra in rats treated with appropriate dopamine agonists provides a cellular marker of D1 receptor supersensitivity. D1 receptors are positively linked to adenylate cyclase and therefore to cAMP-dependent protein kinase. Because expression of the c-fos gene in response to cAMP- and Ca2+/calmodulin-regulated protein kinases depends on phosphorylation of cAMP-response element-binding protein (CREB) at Ser-133, we examined CREB phosphorylation after dopaminergic stimulation in cultured striatal neurons and in the striatum of rats after unilateral 6-hydroxydopamine ablation of the substantia nigra. Using an antiserum specific for CREB phosphorylated at Ser-133, we found that dopamine increases CREB phosphorylation in cultured striatal neurons. This effect was blocked by a D1 antagonist. L-Dopa produced marked CREB phosphorylation in striatal neurons in rats ipsilateral, but not contralateral, to a 6-hydroxydopamine lesion. This response was blocked by a D1 antagonist, but not a D2 antagonist, and was reproduced by a D1 agonist, but not a D2 agonist. These findings are consistent with the hypothesis that D1 receptor supersensitivity is associated with upregulated activity of cAMP-dependent or Ca2+/calmodulin-dependent protein kinases, or both, following dopamine denervation of striatal neurons.
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PMID:6-Hydroxydopamine lesions of rat substantia nigra up-regulate dopamine-induced phosphorylation of the cAMP-response element-binding protein in striatal neurons. 793 19

The cAMP-responsive element modulator (CREM) gene encodes a family of transcriptional regulators that bind to promoter sequences activated by increased intracellular cAMP levels. Both activators and repressors are generated by alternative splicing and alternative translational initiation. During the development of male germ cells, there is a switch in the transcripts generated by CREM. Specifically, from the prophase of meiosis, there is an increase in the CREM tau activator transcript. Here we present results showing that expression of the CREM activator protein is restricted to postmeiotic germ cells. We show that CREM tau is efficiently phosphorylated at a serine residue at position 117 by the protein kinase-A endogenous to germ cells, indicating that it constitutes a natural target of the adenylyl cyclase pathway during spermatogenesis. Phosphorylation of serine-117 turns CREM tau into a powerful activator. The rise in CREM tau protein coincides with the transcriptional activation of several genes. We show that CREM tau efficiently binds to CREs present in the promoters of these genes, suggesting that they could constitute down-stream targets of CREM. We have analyzed in more detail the regulation of one of these genes, the male germ cell-specific RT7. The RT7 promoter is cAMP inducible and activated by CREM tau in transfection assays. The RT7 promoter is efficiently transcribed in vitro with nuclear extracts from seminiferous tubules. CREM-specific antibodies block RT7 in vitro transcription, implicating a role for CREM tau in a cascade of transcriptional events during spermatogenesis.
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PMID:Induction of CREM activator proteins in spermatids: down-stream targets and implications for haploid germ cell differentiation. 811 65

The transcriptional transactivational activities of the phosphoprotein cAMP-response element-binding protein (CREB) are activated by the cAMP-dependent protein kinase A signaling pathway. Dimers of CREB bind to the palindromic DNA element 5'-TGACGTCA-3' (or similar motifs) called cAMP-responsive enhancers (CREs) found in the control regions of many genes, and activate transcription in response to phosphorylation of CREB by protein kinase A. Earlier we reported on the cyclical expression of the CREB gene in the Sertoli cells of the rat testis that occurred concomitant with the FSH-induced rise in cellular cAMP levels and suggested that transcription of the CREB gene may be autoregulated by cAMP-dependent transcriptional proteins. We now report the structure of the 5'-flanking sequence of the human CREB gene containing promoter activity. The promoter has a high content of guanosines and cytosines and lacks canonical TATA and CCAAT boxes typically found in the promoters of genes in eukaryotes. Notably, the promoter contains three CREs and transcriptional activities of a promoter-luciferase reporter plasmid transfected to placental JEG-3 cells are increased 3- to 5-fold over basal activities in response to either cAMP or 12-O-tetradecanoyl phorbol-14-acetate, and give 6- to 7-fold responses when both agents are added. The CREs bind recombinant CREB and endogenous CREB or CREB-like proteins contained in placental JEG-3 cells and also confer cAMP-inducible transcriptional activation to a heterologous minimal promoter. Our studies suggest that the expression of the CREB gene is positively autoregulated in trans.
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PMID:The promoter of the gene encoding 3',5'-cyclic adenosine monophosphate (cAMP) response element binding protein contains cAMP response elements: evidence for positive autoregulation of gene transcription. 838 Oct 74

The cAMP response element modulator (CREM) gene encodes multiple activators and repressors of cAMP-responsive transcription. Differential splicing generates a developmental switch in CREM function during spermatogenesis, while the use of an alternative promoter is responsible for the production of a cAMP-inducible transcriptional repressor, ICER (inducible cAMP early repressor). The ICER promoter is strongly inducible by cAMP because of the presence of four tandemly repeated cAMP response elements. Furthermore, ICER negatively autoregulates the ICER promoter activity, thus generating a feedback loop. CREM constitutes an early response gene of the cAMP pathway in several neuroendocrine cells. We have previously shown that CREM is highly expressed in the adult rat pineal gland at nighttime. Here, we show that the only additional site of rhythmic ICER expression within the photoneuroendocrine system is the lamina intercalaris. Ontogenetically, the ICER day-night switch and cAMP inducibility mature in the pineal gland at the end of the first postnatal week. Importantly, this correlates with the onset of melatonin synthesis and the establishment of functional adrenergic innervation. At this developmental phase we document a significant increase in protein kinase A levels, thus suggesting that ICER inducibility reflects a complete maturation of the cAMP-dependent signaling pathway at the nuclear level.
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PMID:Developmental maturation of pineal gland function: synchronized CREM inducibility and adrenergic stimulation. 859 16

Single gene mutants of Drosophila that are defective in learning/memory processes have increased substantially our understanding of the physiology, biochemistry, and anatomy underlying conditioned behaviors. Drosophila learning mutants can be separated into two general classes, those with structural defects in the brain and those without (conditioning mutants) any obvious brain alterations. From studies of brain structural mutants, two neuroanatomic areas have merged as important for normal conditioned behavior: the mushroom bodies and the central complex. Biochemical and molecular genetic studies of the conditioning mutants have implicated numerous types of molecules in learning, but the adenosine 3',5'-cyclic monophosphate (cAMP) second messenger pathway has emerged as especially important. Five different genes in this pathway, amnesiac (a product similar to adenylate cyclase activating peptides), dunce (cAMP phosophodiesterase), rutabaga (adenylyl cyclase), DCO (protein kinase A), and dCREB2 (cAMP-response element binding protein), have proven important for normal learning. The products of many of these learning mutants are enriched in mushroom bodies, which highlight the importance of mushroom bodies for normal learning and the cAMP second messenger cascade for the physiology of mushroom body cells in their role(s) underlying learning. Physiological studies of the mutants have demonstrated that plastic properties of synaptic transmission, including facilitation and posttetanic potentiation, are abnormal in the mutants. An appendix describing the currently used paradigms to test Drosophila behavior is included.
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PMID:Physiology and biochemistry of Drosophila learning mutants. 861 59

To achieve a better understanding of the mechanism of transactivation by Tax of human T-cell leukemia virus type 1 Tax-responsive element 1 (TRE-1), we developed a genetic approach with Saccharomyces cerevisiae. We constructed a yeast reporter strain containing the lacZ gene under the control of the CYC1 promoter associated with three copies of TRE-1. Expression of either the cyclic AMP response element-binding protein (CREB) or CREB fused to the GAL4 activation domain (GAD) in this strain did not modify the expression of the reporter gene. Tax alone was also inactive. However, expression of the reporter gene was induced by coexpression of Tax and CREB. This effect was stronger with the GAD-CREB fusion protein. Analysis of different CREB mutants with this genetic system indicated that the C-terminal 92 amino acid residues, which include the basic domain and the leucine zipper, are necessary and sufficient to mediate transactivation by Tax. To identify cellular proteins binding to TRE-1 in a Tax-dependent manner, this strain was also used to screen a library of human cDNAs fused to GAD. Of five positive clones isolated from 0.75 x 10(6) yeast colonies, four were members of the CREB/activating transcription factor (ATF) family: CREB, two isoforms of the cyclic AMP-responsive element modulator (CREM), and ATF-1. Interestingly, these three proteins can be phosphorylated by protein kinase A and thus form a particular subgroup within the CREB/ATF family. Expression of ATF-2 in S. cerevisiae did not activate TRE-1 in the presence of Tax. This shows that in a eukaryotic nucleus, Tax specifically interacts with the basic domain-leucine zipper region of ATF-1, CREB, and CREM. The fifth clone identified in this screening corresponded to the Ku autoantigen p70 subunit. When fused to GAD, the C-terminal region of Ku was able to activate transcription via TRE-1 but this activation was not dependent on Tax.
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PMID:Genetic characterization of transactivation of the human T-cell leukemia virus type 1 promoter: Binding of Tax to Tax-responsive element 1 is mediated by the cyclic AMP-responsive members of the CREB/ATF family of transcription factors. 862 84

The activation of the magnocellular oxytocin system by different physiological stimuli will require specific genomic responses that may or may not reflect the electrical and short-term secretory activity of the neurones. One of the main determinants of synthetic activity is the rate of transcription and this can be altered acutely by the action of inducible transcription factors (iTFs). Having shown that the expression of two iTFs, the protein products of the c-fos and c-jun genes, does not correlate directly to the electrical activity of magnocellular neurones (Luckman et al., 1994) the expression of leucine zipper iTF mRNAs was measured following different stimuli using combined radioactive and non-radioactive in situ hybridization. Stimuli that are dependent on brainstem afferents such as parturition and systemic injection of cholecystokinin caused co-induction of c-fos and c-jun in oxytocin neurones. Mild osmotic stimulation, a stimulus dependent on forebrain afferents, induced c-fos, fos B and jun B, but inhibited c-jun. Similar patterns of leucine zipper iTF expression have been noted in cultured cells following activation of protein kinases C and A, respectively. Input from the brainstem appears to be mediated, at least in part, by noradrenaline acting on alpha(1)-adrenoceptors. While the forebrain inputs are not well characterised they do appear to include a glutaminergic component that may activate a variety of receptors. Interestingly, another member of the leucine zipper family known to be induced by protein kinase A, inducible cAMP early repressor (ICER), that was previously thought to be restricted to the pineal gland, was expressed in magnocellular neurones following osmotic stimulation but not parturition. Furthermore, the differential expression of iTFs is not limited to this family. Osmotic stimulation influences c-fos, but it also causes the expression of NGFI-A and NGFI-B, members of the zinc finger family of iTFs. By contrast, an acute suckling stimulus is able to induce c-fos and NGFI-A, but not nGFI-B.
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PMID:Stimulus-specific expression of inducible transcription factors in identified oxytocin neurones. 871 50

Cyclic AMP-responsive genes are regulated both positively and negatively by a number of constitutively expressed nuclear proteins. These proteins bind to cAMP-responsive DNA elements in their target genes and they are activated by protein kinase A-mediated phosphorylation. The cAMP response element modulator gene encodes for several constitutively expressed products. However, a second intronic promoter within the gene is inducible and produces another negatively acting transcription factor, inducible cAMP early repressor (ICER). ICER shows a diurnal pattern of expression in the pineal gland, but to date it has not been noted elsewhere in the brain. Here we show expression of ICER mRNA in hypothalamic magnocellular neurons following osmotic stimulation over a time course consistent with a modulatory effect on the expression of other immediate-early genes, such as c-fos. However, since ICER was not present in magnocellular neurons during parturition, its presence is not a prerequisite for the transient expression of c-fos.
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PMID:Expression of inducible cAMP early repressor (ICER) in hypothalamic magnocellular neurons. 875 Aug 26

Members of the CREB/CREM/ATF family of transcription factors either enhance or repress transcription after binding to the cAMP response elements (CREs) of numerous genes. The rat gene for tyrosine hydroxylase (TH) bears a canonical CRE, at base pairs -38 through -45 from the transcription initiation site, that is essential for basal and cAMP-stimulated transcription (Kim, K.-S., Lee, M. K., Carroll, J., and Joh, T. H. (1993) J. Biol. Chem. 268, 15689-15695; Lazaroff, M., Patankar, S., Yoon, S. O., and Chikaraishi, D. M. (1995) J. Biol. Chem. 270, 21579-21589). The current study identifies CRE-binding proteins induced in pharmacological paradigms characterized by TH activation. PC12- and rat adrenal gland-derived nuclear proteins retarded a TH-CRE oligonucleotide in gel mobility shift assays with virtually identical patterns. These differed substantially from patterns exhibited by extracts from locus ceruleus or from neuroblastoma (SK-N-BE()C) and locus ceruleus-derived (CATH.a) cell lines. Forskolin stimulation of PC12 cells and reserpine treatment of rats increased, in nuclear extracts derived from cells and adrenal glands, respectively, the amount of a fast moving CRE/protein complex that was supershifted by an anti-CREM antibody. Subsequent Western, Northern, and polymerase chain reaction analyses indicated that a specific member of the CREM family, the inducible cAMP early repressor (ICER), was strongly induced in both systems. Cotransfection of PC12 cells with TH2400CAT plasmid and the expression vector pCMV-ICER-Ib demonstrated that ICER efficiently represses the transcriptional activity of the TH gene promoter. In addition, PKA-stimulated transcriptional activity of the promoter was effectively suppressed by ICER. These results suggest that ICER can modulate cAMP-stimulated transcription of the TH gene and provide a model accounting for rapid reversal of increased TH transcription following elevations in cAMP.
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PMID:Inducible cAMP early repressor can modulate tyrosine hydroxylase gene expression after stimulation of cAMP synthesis. 881 Mar 3

We recently showed that mesangial cells treated with high glucose plus TGF beta or PMA demonstrated activation of a cAMP-response element (CRE) located in the 5' flanking region of the fibronectin gene. Gel shift mobility assays with a CRE oligonucleotide revealed multiple complexes that did not change in mobility or abundance under conditions of high glucose plus TGF beta or PMA. Here we show that treatment with cycloheximide to inhibit protein synthesis also did not change the DNA/protein complexes. These observations led us to conclude that post-translational modification of transcription factors may be responsible for the activation of the fibronectin gene observed under our experimental conditions. We identified the proteins complexed to CRE as CRE binding protein (CREB) and activating factor 1 (ATF1). This was accomplished by supershift assays and immunoblots. Two hours of high glucose plus TGF beta or 30 minutes of PMA caused a twofold elevation in phosphorylated CREB. Neither high glucose nor TGF beta alone caused phosphorylation of CREB. ATF-1 was not phosphorylated. We also show that high glucose plus TGF beta and PMA activated protein kinase C alpha; however, none of the agents tested stimulated intracellular cAMP levels, indicating that phosphorylation of CREB was independent of protein kinase A activation. These results demonstrate cross-talk between the protein kinase C and protein kinase A pathways in that agents which activate the protein kinase C pathway can stimulate phosphorylation of proteins that commonly serve as substrates for protein kinase A.
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PMID:Phosphorylation of cAMP responsive element binding protein after treatment of mesangial cells with high glucose plus TGF beta or PMA. 887 54


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