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)

The tissue-specific extinguisher locus TSE1, a dominant negative regulator of transcription in somatic cell hybrids, acts via a cAMP response element (CRE) to repress activity of a hepatocyte-specific enhancer. Guided by the antagonism between TSE1 and cAMP-mediated signal transduction, we identified the regulatory subunit RI alpha of protein kinase A (PKA) as the product of the TSE1 locus. The evidence derives from concordant expression of RI alpha mRNA and TSE1 genetic activity, high resolution mapping of the RI alpha gene and TSE1 on human chromosome 17, and the ability of a transfected RI alpha cDNA to generate a phenocopy of TSE1-mediated extinction. The mechanism of TSE1/RI alpha-mediated extinction involves repression of basal PKA activity, reduced phosphorylation of CREB at Ser-133, and a corresponding reduction of in vivo protein binding at the target CRE.
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PMID:The tissue-specific extinguisher locus TSE1 encodes a regulatory subunit of cAMP-dependent protein kinase. 183 37

The cyclic AMP (cAMP) response element-binding protein (CREB) has been demonstrated to be a key mediator of cellular promoter response to cAMP. The binding site for this protein in many cellular cAMP inducible promoters (CRE) contains the palindrome sequence TGACGTCA, which contains two half-sites for CREB binding. A related promoter element, with the core sequence TGACG, has significant homology to an AP1-binding site and contains only one half-site for CREB binding. A group of factors known as activating transcription factors (ATF) have been found to bind to the latter and related sequences found upstream of early adenovirus promoters induced by E1A, and these factors are highly homologous to the CREB protein. We wished to characterize CREB, c-jun, and c-fos binding to these sites in the somatostatin gene (CRE) and in the adenovirus early region 3 promoter (E3/ATF). Oligonucleotides complementary to each of these sites were used in gel retardation assays with in vitro-translated CREB protein. These studies indicated that CREB bound primarily as a dimer to both a single and two half-sites, though there was increased affinity to the double compared with the single half-site. The c-jun and c-fos proteins also bound to both the somatostatin CRE- and E3/ATF-binding sites, but CREB did not bind to AP1 recognition sites nor was it capable of forming heterodimers with either c-jun or c-fos. Truncations of the CREB protein, which eliminated regions of the protein containing consensus sites for phosphorylation by protein kinase A, protein kinase C, and casein kinase II, bound to both the CRE and ATF sites, indicating that these consensus sites were not essential for DNA binding or dimer formation. Transfection of CREB and protein kinase A expression constructs into F9 cells with promoters containing either a single or two half-sites for CREB binding indicated that CREB was capable of similar levels of activation of these constructs. However, the fold activation by CREB was higher for constructs containing a single half-site compared with those containing two half-sites. These results demonstrate that multiple mechanisms may regulate CREB binding, including variations in the sequences in the promoter-binding site and the presence of related DNA-binding proteins.
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PMID:CREB regulation of cellular cyclic AMP-responsive and adenovirus early promoters. 197 51

The TGACGTCA (CRE) motif required for function by a number of cellular (somatostatin, enkephalin, alpha-human chorionic gonadotropin) and viral (Ad5 E1A-inducible, HTLV-1 TAX-inducible) genes is the site of interaction of multiple sequence-specific complexes. A protocol has been developed for the fractionation and purification of these activities. We report here the purification from HeLa nuclear extracts of a novel 120-kDa polypeptide which by Southwestern blots, gel retardation, and UV cross-linking assays displays CRE-specific binding. The CRE-affinity purified 120-kDa protein displays properties distinct from those of the 43-kDa CREB/ATF polypeptide. The 120-kDa protein is readily phosphorylated in vitro by protein kinase C but not by protein kinase A, suggesting that this molecule may mediate cellular signals distinct from the cAMP-responsive pathway. In vitro transcription-complementation assays utilizing the purified 120-kDa protein failed to transactivate the cAMP-responsive somatostatin promoter suggesting that the mode of action of this 120-kDa polypeptide may require an activation step distinct from the cAMP-signaling pathway.
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PMID:Identification and purification of a novel 120-kDa protein that recognizes the cAMP-responsive element. 213 55

In both vertebrates and invertebrates, long-term memory differs from short-term in requiring protein synthesis during training. Studies of the gill and siphon withdrawal reflex in Aplysia indicate that similar requirements can be demonstrated at the level of sensory and motor neurons which may participate in memory storage. A single application of serotonin, a transmitter that mediates sensitization, to individual sensory and motor cells in dissociated cell cultures leads to enhanced transmitter release from the sensory neurons that is independent of new macromolecular synthesis. Five applications of serotonin cause a long-term enhancement, lasting one or more days, which requires translation and transcription. Prolonged application or intracellular injection into the sensory neuron of cyclic AMP, a second messenger for the action of serotonin, also produce long-term increases in synaptic strength, suggesting that some of the gene products important for long-term facilitation are cAMP-inducible. In eukaryotic cells, most cAMP-inducible genes so far studied are activated by the cAMP-dependent protein kinase (A kinase), which phosphorylates transcription factors that bind the cAMP-responsive element TGACGTCA. The cAMP-responsive element (CRE) binds a protein dimer of relative molecular mass 43,000, the CRE-binding protein (CREBP), which has been purified and shown to increase transcription when phosphorylated by the A kinase. Here we show that extracts of the Aplysia central nervous system and extracts of sensory neurons contain a set of proteins, including one with properties similar to mammalian CREBPs, that specifically bind the mammalian CRE sequence. Microinjection of the CRE sequence into the nucleus of a sensory neuron selectively blocks the serotonin-induced long-term increase in synaptic strength, without affecting short-term facilitation. Taken together, these observations suggest that one or more CREB-like transcriptional activators are required for long-term facilitation.
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PMID:Injection of the cAMP-responsive element into the nucleus of Aplysia sensory neurons blocks long-term facilitation. 214 68

The transcription regulation of many hormone genes is modulated by intracellular second messengers such as cAMP. The cAMP response element binding protein, CREB, binds to the 8 base pair CRE enhancer, TGACGTCA, that is found in the 5'-flank of certain genes including those for somatostatin and the alpha-subunit of human chorionic gonadotropin. The recent characterization of CREB and CREB-related cDNA clones, combined with Southwesterns and Northern blot analyses, reveals a family of transcription factors that dimerize via a leucine zipper motif and bind to the CRE through positively charged basic regions. The CREB cDNA encoding a 327 residue protein is transcriptionally activated via phosphorylation by protein kinases, including the cAMP-dependent protein kinase-A.
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PMID:Characterization of a cAMP-regulated enhancer-binding protein. 214 88

The mechanism by which the calcium influx signal, triggered by membrane depolarization, is transduced to the nucleus to activate c-fos proto-oncogene transcription has been characterized. A calcium response element (CaRE) that is indistinguishable from a cAMP response element (CRE) mediates transcriptional inducibility by depolarization. Its cognate transcription factor CREB is the target for both calcium and cAMP signals. CREB is rapidly phosphorylated in response to depolarization or cAMP, at a site known to be important for the transcriptional activating function of this protein. The convergent effects of calcium and cAMP on CREB activation are mediated by distinct protein kinase signaling pathways. CREB and its binding site, the Ca/CRE, can thus function as a regulatory element that integrates both calcium and cAMP signals in the control of gene expression.
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PMID:Membrane depolarization and calcium induce c-fos transcription via phosphorylation of transcription factor CREB. 215 71

Phenotypically distinct islet tumor cell lines may recapitulate certain of the developmental pathways of normal islet cell differentiation by expressing a combinatorial set of positively and negatively acting DNA-binding proteins to allow for the programmed expression of genes encoding polypeptide hormones. The structure of one of these DNA-binding proteins, a cyclic AMP-responsive protein (CREB) that binds specific DNA regulatory elements in the somatostatin gene, has been deduced from the sequence of a cloned cDNA. The CREB protein contains a DNA-binding domain separate from a cAMP-dependent protein kinase A activation domain. Further characterizations of the genes encoding the DNA-binding proteins should help to elucidate the cellular processes involved in islet cell differentiation and the genesis of tumors.
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PMID:Factors that determine cell-specific gene expression in pancreatic endocrine tumor cells. 255 19

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.
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PMID:Induction of proto-oncogene fos transcription through the adenylate cyclase pathway: characterization of a cAMP-responsive element. 285 Sep 67

Early in adenovirus infection, the E1A (early region 1A) oncogene products trans-activate the other early viral transcription units, as well as some cellular promoters. The mechanism by which E1A elicits its activity is still unknown. In this report, I show that the adenovirus E2a and E3 promoters are cAMP inducible in rat pheochromocytoma PC12 cells and that this activation requires the presence of the cAMP-dependent protein kinase II. Using deletion mutants of the E2a promoter, it was found that the sequence TACGTCAT located between positions -70 and -77 is involved in both the cAMP response and the E1A trans-activation. Also, in the mutant PC12 cell line A126-2B, which lacks the cAMP-dependent protein kinase II, E1A is still able to activate E2a and E3 promoters. This suggests that E1A products may circumvent the lack of the kinase by activating an alternative signal transduction pathway, which could mimic the effect of agonists of adenylate cyclase. I propose that E1A is capable of modifying by phosphorylation, either directly or indirectly, the transcription factor that binds the ACGTCA motif. Such a factor, termed ATF (adenovirus transcription factor), has already been characterized and appears to have strong similarities to the transcriptional factor CREB (cAMP responsive element binding protein), which binds homologous sequences in cAMP responsive genes, such as somatostatin and c-fos.
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PMID:Cyclic AMP induction of early adenovirus promoters involves sequences required for E1A trans-activation. 290 26

cAMP has neutrotrophic effects in the nervous system. We have investigated whether there is a correlation between cAMP-induced neurite outgrowth and induction of chromogranin B and synapsin I gene expression. These genes encode marker proteins of distinct populations of vesicles in neurons, neuroendocrine and endocrine cells, and in addition, they contain a cAMP response element (CRE) in their upstream regions, making it likely that cAMP-induced neuronal differentiation might be accompanied by increased transcription of these genes. We increased intracellular cAMP levels in neuronal and neuroendocrine cells and analyzed the levels of chromogranin B and synapsin I mRNA. Our data revealed that, while chromogranin B mRNA was in fact induced following cAMP stimulation, synapsin I mRNA was not affected. To analyze the cis-acting sequences, we constructed hybrid genes containing the upstream region of the mouse chromogranin B gene fused to a reporter gene. Similar plasmids containing the synapsin I or the glucagon promoter were constructed. Transfections of neuronal and endocrine cells, together with deletion mutagenesis, revealed that the CRE of the chromogranin B gene mediated the effect of cAMP upon transcription. This effect was mimicked by overexpression of the catalytic subunit of the cAMP-dependent protein kinase. In addition, overexpression of the negative-acting CRE-binding protein CREB-2 revealed that the chromogranin B CRE functions as a bifunctional genetic regulatory element in that it mediates basal as well as cAMP-stimulated transcription. Synapsin I gene expression, however, was not induced by either elevated intracellular cAMP concentration or by overexpression of protein kinase A, although a similar pattern of proteins, including CREB, bound to the synapsin I and chromogranin B CRE in vitro. Thus while the CRE element in the chromogranin B gene promoter is responsive to cAMP, the same element, when present in the synapsin I promoter, does not confer cAMP inducibility.
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PMID:Differential regulation of chromogranin B and synapsin I gene promoter activity by cAMP and cAMP-dependent protein kinase. 752 78


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