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)

Cyclic AMP (cAMP) mediates the hormonal stimulation of a number of eukaryotic genes by directing the protein kinase A (PK-A)-dependent phosphorylation of the transcription factor CREB. Somatostatin is one such gene known to be transcriptionally activated by cAMP via CREB. In view of the role somatostatin plays in the regulation of neocortical development, we examined the early expression of CREB mRNA and protein (from E10 to E14) in the rat neocortex by in situ hybridization and immunocytochemistry. mRNA for CREB was detected in all layers of the developing neocortex from E10 to E14. CREB immunoreactivity (CREB-IR) was also observed in most cortical cells by E10. However, the number of CREB-immunoreactive nuclei decreased thereafter, and on E14 there were immunoreactive cells only in the preplate. A moderate amount of somatostatin mRNA was observed on E16 in layer I, which is produced from the preplate. This stage specific expression of the CREB protein in the developing neuroepithelium suggests that by regulating transcription of some peptides including somatostatin, CREB plays a role in cortical development.
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PMID:A developmental study of cyclic AMP-response element binding protein (CREB) by in situ hybridization histochemistry and immunocytochemistry in the rat neocortex. 792 74

We report that the small tumor (small-t) antigen of simian virus 40 (SV40) forms complexes with nuclear protein phosphatase 2A (PP2A) and regulates the phosphorylation and transcriptional transactivation function of the cyclic AMP (cAMP)-regulatory element binding protein (CREB). PP2A coimmunoprecipitated with small t from nuclear extracts from HepG2 cells expressing small t or from rat liver nuclear extracts to which recombinant small t was added. Protein phosphatase 1 was not detected in small-t immunoprecipitates. In HepG2 cells expressing small t, dibutyryl-cAMP (Bt2cAMP) stimulated the phosphorylation of CREB 65-fold, whereas CREB phosphorylation was stimulated only 5- to 8-fold by Bt2cAMP in cells not expressing small t. Small t also inhibited the dephosphorylation of cAMP-dependent protein kinase (PKA)-phosphorylated CREB in rat liver nuclear extracts. In cells expressing small t, Bt2cAMP-stimulated transcription from the phosphoenolpyruvate carboxykinase (PEPCK) gene promoter was enhanced over the level of transcription from the PEPCK promoter in cells not expressing small t. Small t also enhanced Bt2cAMP-stimulated transcription from a Gal4-responsive promoter in cells expressing a chimeric protein containing the Gal4 DNA-binding domain linked to the CREB transactivation domain. However, small t did not stimulate transcription either from a 5' deletion mutant of the PEPCK promoter that is not able to bind CREB or from the Gal4-responsive promoter in the absence of the Gal4-CREB protein. These data suggest that small t enhances Bt2cAMP-stimulated gene transcription by inhibiting the dephosphorylation of PKA-phosphorylated CREB by nuclear PP2A. These findings support previous observations that nuclear PP2A is the primary phosphatase that dephosphorylates PKA-phosphorylated CREB.
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PMID:Simian virus 40 small tumor antigen inhibits dephosphorylation of protein kinase A-phosphorylated CREB and regulates CREB transcriptional stimulation. 806 21

The human T-cell leukemia virus type I (HTLV-I) Tax protein increases the DNA binding activity of a number of different host cell transcription factors, including the cyclic AMP response element binding protein (CREB). We have performed quantitative studies of CREB binding in the presence and absence of Tax in an attempt to gain insight into the mechanism of the Tax effect. Enhancement of binding occurred over a wide range of CREB concentrations, but sharply increased at the lowest concentrations tested. The data are best explained by a two-step binding model where Tax changes the apparent equilibrium constants for both a CREB-CREB dimerization step and a (CREB)2-DNA binding step. We used the model to perform a quantitative analysis of the binding of CREB to DNA that had been mutated at positions flanking the core CREB recognition site. Results suggest that there are altered or more extensive DNA-protein contacts at these positions in the presence of Tax. We also used the model to analyze differences in the interaction of Tax with nonphosphorylated and protein kinase A-phosphorylated CREB protein. There was no significant change in the behavior of CREB upon phosphorylation.
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PMID:Quantitative studies of the effect of HTLV-I Tax protein on CREB protein--DNA binding. 806 35

We established the cis-acting elements which mediate cAMP responsiveness of the human growth hormone (hGH) gene in transiently transfected rat anterior pituitary tumor GC cells. Analysis of the intact hGH gene or hGH 5'-flanking DNA (5'-FR) coupled to the hGh cDNA or chloramphenicol acetyltransferase or luciferase genes, indicated that cAMP primarily stimulated hGH promoter activity. Cotransfection of a protein kinase A inhibitory protein cDNA demonstrated that the cAMP response was mediated by protein kinase A. Mutational analysis of the hGH promoter identified two core cAMP response element motifs (CGTCA) located at nucleotides -187/-183 (distal cAMP response element; dCRE) and -99/-95 (proximal cAMP response element; pCRE) and a pituitary-specific transcription factor (GHF1/Pit1) binding site at nucleotides -123/-112 (dGHF1) which were required for cAMP responsiveness. GHF1 was not a limiting factor, since overexpression of GHF1 in cotransfections increased basal but not forskolin induction levels. Gel shift analyses indicated that similar, ubiquitous, thermostable protein(s) specifically bound the pCRE and dCRE motifs. The CGTCA motif-binding factors were cAMP response element binding protein (CREB)/activating transcription factor-1 (ATF-1)-related, since the DNA-protein complex was competed by unlabeled CREB consensus oligonucleotide, specifically supershifted by antisera to CREB and ATF-1 but not ATF-2, and was bound by purified CREB with the same relative binding affinity (pCRE < dCRE < CREB) and mobility as the GC nuclear extract. UV cross-linking and Southwestern blot analyses revealed multiple DNA-protein interactions of which approximately 100- and approximately 45-kDa proteins were predominant; the approximately 45-kDa protein may represent CREB. These results indicate that CREB/ATF-1-related factors act coordinately with the cell-specific factor GHF1 to mediate cAMP-dependent regulation of hGH-1 gene transcription in anterior pituitary somatotrophs.
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PMID:Two CGTCA motifs and a GHF1/Pit1 binding site mediate cAMP-dependent protein kinase A regulation of human growth hormone gene expression in rat anterior pituitary GC cells. 829 29

Several lines of evidence indicate that cyclic AMP (cAMP) induces oligodendrocytes differentiation. However, the mechanism(s) of this stimulation remains unknown. Because in several cell types the transcriptional activity of various cAMP-responsive genes is regulated through a cis-acting DNA sequence known as cAMP response element (CRE), we investigated the possible presence of a CRE binding (CREB) protein in myelinating oligodendrocytes. A double-stranded oligonucleotide containing a tandem repeat of the CRE sequence was labeled with T4 kinase in the presence of [32P]ATP and then incubated with a nuclear protein extract from 14-day-old rat brain oligodendrocytes. The reaction mixture was then electrophoresed on nondenaturing polyacrylamide gels. The results indicated the presence of a protein that specifically binds to the CRE sequence. The results were supported by southwestern blotting assays in which the CRE probe bound to a approximately 45-kDa protein species. In separate experiments, it was shown that the 45-kDa protein can be phosphorylated in vitro by the catalytic subunit of protein kinase A. Developmental analysis of CREB protein expression indicated a peak at 14 days of age, preceding the peak of myelinogenesis.
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PMID:Presence of cyclic AMP response element-binding protein in oligodendrocytes. 849 19

We previously reported that microinjection of purified Ras protein stimulated DNA synthesis in quiescent Wistar rat thyrocytes and that TSH (TSH)-stimulated DNA synthesis was Ras-dependent. In contrast to these results, microinjection of cellular or oncogenic Ras significantly reduced TSH-stimulated thyroglobulin (Tg) expression, a marker of thyrocyte differentiation. Microinjection of a dominant inhibitory Ras mutant had no effect on TSH-stimulated Tg expression. As the Tg promoter is cAMP-responsive and Ras was previously reported to interfere with entry of catalytic (C) subunit of the cAMP-dependent protein kinase into the nucleus, experiments were performed to assess the effects of Ras on cAMP-mediated signaling. Microinjection of either cellular or oncogenic Ras had no effect on TSH-stimulated entry of C subunit into the nucleus. Consistent with these data, Ras did not reduce TSH-stimulated cAMP response element binding protein phosphorylation, or cAMP response element-regulated gene expression. These results demonstrate that Ras exerts differential effects on TSH signaling; Ras increases TSH-stimulated DNA synthesis and decreases TSH-induced Tg expression. Moreover, the mechanism through which Ras induces Tg expression lies distal to entry of C subunit into the nucleus, cAMP response element binding protein phosphorylation, and cAMP response element-regulated gene expression.
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PMID:Ras inhibits thyroglobulin expression but not cyclic adenosine monophosphate-mediated signaling in Wistar rat thyrocytes. 853 48

Estrogen treatment of ovariectomized rats rapidly increases immunoreactivity for the phosphorylated form of the cAMP response element binding protein (CREB)in neurons of the preoptic area and the bed nucleus of the stria terminalis. These effects were detected within 15 minutes after estrogen exposure. Since the antisera used for these studies detect CREB phosphorylation at ser133, which is important for transcriptional activation these data provide a possible explanation for estrogen's effects on neuronal genes lacking estrogen response elements (EREs) but which contain cAMP response elements (CREs). These data also provide evidence for non-genomic effects of steroid hormones involving protein kinase associated signal transduction pathways traditionally associated with effects at the cell membrane.
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PMID:Estrogen rapidly induces the phosphorylation of the cAMP response element binding protein in rat brain. 861 62

We have recently shown that infection of Epstein-Barr virus (EBV) genome-positive B cells by human herpesvirus 6 (HHV-6) results in the expression of the immediate-early EBV Zebra gene, followed by virus replication (L. Flamand, I. Stefanescu, D. V. Ablashi, and J. Menezes, J. Virol. 67:6768-6777, 1993). Here we show that HHV-6 upregulates Zebra gene transcription through a cyclic AMP-responsive element (CRE) located within the Zebra promoter (Zp). Using human B- or T-cell lines transfected with ZpCat reporter gene constructs, we demonstrate that a region designated the ZII domain of Zp is the target of HHV-6 transactivation. Mutation of the consensus AP-1/CRE site within ZII abolished the inducibility of Zp by HHV-6, whereas positioning of the ZII domain upstream of the beta-globin minimal promoter conferred responsiveness following HHV-6 infection. Binding of these factors to ZII was prevented by oligonucleotides containing CRE but not by AP-1 consensus sequences. Antibodies against CRE-binding (CREB) protein but not against c-Fos or c-Jun were able to supershift the DNA-protein complex, identifying the nature of the transcription factor which binds to ZII as a member of the CREB family of proteins. Finally, transfection of CREB protein and protein kinase A expression vectors were found to activate Zp in Jurkat cells, suggesting that phosphorylated form of CREB protein can play a determining role in the EBV reactivation process.
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PMID:Cyclic AMP-responsive element-dependent activation of Epstein-Barr virus zebra promoter by human herpesvirus 6. 862 1

Efficient transcription and replication of the bovine leukemia virus (BLV) genome require both the viral long terminal repeat (LTR) and the virus-coded transcriptional activator Tax, which functions through a 21-bp sequence (Tax-responsive element [TxRE]) which is repeated three times within the LTR. Since Tax does not bind directly to DNA, host cell transcription factors play a central role in BLV expression. Electrophoretic mobility shift assays with nuclear extracts prepared with infected bovine B lymphocytes revealed five TxRE-specific complexes (C1, C2, C3, C4, and C5). Here, by using a UV-induced indirect labeling technique (UV cross-linking) in conjunction with mobility shift assays, eight major polypeptides of 31, 33, 42, 46, 51, 57, 87, and 119 kDa were identified within these five complexes. Immunoprecipitation experiments identified the 57- and 119-kDa proteins as cyclic AMP response element-binding (CREB) proteins, the 46- and 51-kDa proteins as activating transcription factor-1 (ATF-1), and the 87-kDa as protein ATF-2. All of these proteins (except the ATF-1 protein of 51 kDa) belong to the complex C1, which is the major complex identified in freshly isolated BLV-infected lymphocytes from cattle with persistent lymphocytosis. In transient-cotransfection experiments, these three transcription factors were able to activate LTR-directed gene expression in the presence of protein kinase A or Ca2+/calmodulin-dependent protein kinase IV. CREB protein, ATF-1, and ATF-2 thus appear to be the major transcription factors involved in the early stages of viral expression.
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PMID:The CREB, ATF-1, and ATF-2 transcription factors from bovine leukemia virus-infected B lymphocytes activate viral expression. 862 25

To assess whether the cAMP-dependent protein kinase-A and/or the diacylglycerol-dependent protein kinase C (PKC) pathways play important roles in the activation of CRF neurons in vivo under physiological conditions, we tested the effect of microinjection of 8-bromo-cAMP (8-Br-cAMP) or 12-O-tetradecanoyl phorbol 13-acetate (TPA) into both paraventricular nuclei (PVN) of the hypothalamus in conscious rats. Both 8-Br-cAMP and TPA increased plasma ACTH concentrations and the POMC messenger RNA (mRNA) concentrations in the anterior pituitary. While injection of 8-Br-cAMP also increased CRF mRNA concentrations in hypothalamic tissue containing the PVN, TPA injection had no effect on CRF mRNA concentrations there. During insulin-induced hypoglycemia, which stimulates CRF gene expression and release, c-fos and c-jun mRNA increases in the hypothalamic tissue preceded the increase in the CRF mRNA level after insulin-induced hypoglycemia. Antisense oligodeoxyribonucleotides (oligos) directed against c-fos, c-jun, or the cAMP response element binding protein (CREB) mRNA were injected into both PVN before insulin-induced hypoglycemia to assess whether activator protein-1 or CREB mediates transcriptional activation of CRF during hypoglycemia. Only antisense oligo against CREB mRNA reduced the CRF mRNA level after insulin-induced hypoglycemia. These results suggest that protein kinase A may transduce intracellular signals in CRF neurons under physiological conditions and raises the possibility that CREB may be involved in stress-induced CRF gene expression.
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PMID:Major role of 3',5'-cyclic adenosine monophosphate-dependent protein kinase A pathway in corticotropin-releasing factor gene expression in the rat hypothalamus in vivo. 864 Nov 91


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