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)

We have recently shown that doxorubicin (Dox), an antineoplastic drug and an inhibitor of terminal differentiation of myogenic and adipogenic cells, induces expression of Id, a gene encoding a helix-loop-helix transcriptional inhibitor. In this study we have investigated the molecular mechanisms underlying Dox-induced Id2A expression. We have also attempted to determine whether the genetic responses to Dox are related to the UV response, a well-characterized set of reactions to UV and DNA-damaging compounds that is partly mediated by AP-1. Transient transfection of a series of deletions and point mutation derivatives of the human Id2A promoter sequence shows that two closely spaced and inverted short elements similar to an activating transcription factor (ATF) binding site or a cyclic AMP response element (CRE) are necessary and sufficient for a full response to Dox. We refer to this element as the IdATF site. Sequences containing an IdATF site conferred Dox inducibility on a minimal heterologous promoter. An electrophoretic mobility shift assay showed nuclear proteins specifically interacting with the IdATF sequence. While oligonucleotides containing either legitimate ATF/CRE or AP-1 binding sequences competed for binding, antibody supershift experiments suggested that neither CREB/ATF-1 nor AP-1 are major factors binding to IdATF. Several independent criteria suggest that Dox inducibility was independent of Ca2+/phospholipid-dependent protein kinase (protein kinase C), cyclic AMP-dependent protein kinase (protein kinase A), and tyrosine kinase. Moreover, we found that Dox also induces transcription from promoters of immediate-early genes through an AP-1-independent pathway. Taken together, our results suggest that Dox elicits a novel genetic response distinct from the classical UV response.
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PMID:Doxorubicin-induced Id2A gene transcription is targeted at an activating transcription factor/cyclic AMP response element motif through novel mechanisms involving protein kinases distinct from protein kinase C and protein kinase A. 756 91

We have recently shown that a combination of three transcription factors governs the expression of the human transferrin gene in different brain cell types, oligodendrocytes, choroid plexus cells and neuronal cells. It was essential to elucidate the role of each factor in the regulation of transferrin gene transcription. Site-directed mutagenesis and co-transfection experiments in neuronal cells revealed that chicken ovalbumin upstream promoter transcription factor (COUP-TF), which binds to the promoter region I, acts as a repressor. Overexpression of the CCAAT/enhancer binding protein (C/EBP-alpha), which binds to the promoter region II, transactivates the -164/+1 promoter, even enables the -125/+1 region to promote transcription, and synergistically activates transcription in the presence of CREB. The C/EBP-alpha-mediated activation is antagonized by COUP-TF. The positive action of the cAMP response element-binding protein called CRI-BP is revealed by mutations of the central region I site which repress transcription. Moreover addition of dibutyryl cyclic AMP or overexpression of the catalytic subunit of protein kinase A increase transcription from the wild-type and not from the CRI mutant promoter, which shows that CRI-BP is responsible for mediating cAMP stimulation of Tf gene transcription.
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PMID:Transcription of the human transferrin gene in neuronal cells. 761 49

In this report we identify novel spliced forms of cyclic AMP (cAMP) response element-binding protein-1 (CREB-1) mRNA. These forms contained an additional 17 nucleotide insert, which we refer to as the beta exon, located between exons 4 and 7 of the delta, and 5 and 7 of the alpha forms of CREB-1 transcript (nomenclature of Ruppert et al. 1992; EMBO Journal 11, 1503-1512). The inclusion of the beta exon led to the generation of mRNAs in which the frame of CREB-1 sequences 3' to the exon was shifted such that the encoded proteins terminate after the transactivation domain, but before the target serine for cAMP-dependent protein kinase. The beta exon-containing CREB-1 mRNAs were more abundant in tissues that respond poorly to cAMP, suggesting that the generation of beta CREB-1 mRNAs may contribute to the down-regulation of CREB-1 activity and cAMP responsiveness.
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PMID:A novel cyclic AMP response element-binding protein-1 (CREB-1) splice product may down-regulate CREB-1 activity. 761 8

The molecular characterization of GHRH and the GHRH receptor provides a framework for understanding the hypothalamic regulation of pituitary somatotroph function. The signaling events discerned from our investigation of GHRH receptor structure and function form the basis of a model for GHRH action, which is shown in Fig. 20. GHRH interaction with its seven transmembrane domain Gs-coupled receptor on the somatotroph (step 1) leads to the release of growth hormone from secretory granules (step 2), which is likely to involve a G protein-mediated interaction with ion channels, and to a stimulation of intracellular cAMP accumulation (step 3) (Mayo, 1992; Lin et al., 1992; Gaylinn et al., 1993). In several cell types tested, elevated cAMP leads to the phosphorylation and activation of the transcription factor CREB by protein kinase A (Gonzalez and Montminy, 1989; Sheng et al., 1991), and one target gene for CREB action is the pituitary-specific transcription factor Pit-1 or GHF-1 (step 4) (Bodner et al., 1988; Ingraham et al., 1988; McCormick et al., 1990). Pit-1 is a prototypic POU domain protein that is required for the appropriate regulation of the growth hormone gene in somatotroph cells, thus providing a pathway by which a GHRH signal can lead to increased growth hormone synthesis in the pituitary (step 5). In addition, Pit-1 is likely to directly regulate the synthesis of the GHRH receptor (step 6), in that the receptor is not expressed in the pituitary of dw/dw mice that lack functional Pit-1 (Lin et al., 1992), and a cotransfected Pit-1 expression construct can activate the GHRH receptor promoter in transiently transfected CV1 cells (Lin et al., 1993). It remains to be determined whether additional direct regulation of the GHRH receptor gene in response to the cAMP signaling pathway occurs (step 7). The inhibitory peptide somatostatin presumably interacts with this same signaling pathway through G protein-mediated suppression of the cAMP pathway (Tallent and Reisine, 1992; Bell and Reisine, 1993). In agreement with the importance of this signaling system for normal growth, a transgene encoding a nonphosphorylatable mutant CREB protein, which blocks the function of the endogenous CREB protein, is able to cause somatotroph hypoplasia and dwarfism in mice when its expression is targeted to pituitary somatotrophs (Struthers et al., 1991). Several steps in the signaling pathway leading to growth hormone secretion are subject to disruption, resulting in growth hormone deficiency.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Growth hormone-releasing hormone: synthesis and signaling. 774 Jan 67

We have investigated the molecular basis of the variability of the somatostatin cAMP response element (CRE) function in different cell lines. All cells tested contain detectable levels of the CRE-binding protein CREB-1, which mediates transactivation in response to the cAMP-dependent protein kinase (protein kinase-A), in forms that can bind to a somatostatin CRE. Although both responsive and nonresponsive cells contain CREB-1 in heterodimers with activating transcription factor-1 (ATF-1), only cells that allow a cAMP response have a significant proportion of CREB-1 in a homodimeric form. Transfection experiments demonstrate that ATF-1 is capable of antagonizing CREB-1-dependent activation, suggesting that the ability of CREB-1 to mediate a cAMP response is down-regulated by heterodimer formation with ATF-1.
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PMID:Activating transcription factor-1 is a specific antagonist of the cyclic adenosine 3'.5'-monophosphate (cAMP) response element-binding protein-1-mediated response to cAMP. 777 75

Cyclase response elements (CREs) are located in the promoter regions of several neuropeptide and immediate early genes. Activation of the adenylate cylase/cAMP second messenger cascade leads to phosphorylation of CRE-binding proteins (P-CREBs) which bind to CREs in the promoter regions of these genes and alter their rate of transcription. We have previously reported an increase in striatal immunoreactivity for P-CREB (phosphorylated on Ser-133) and Fos following intracerebroventricular (ICV) injection of H2O-soluble forskolin, a direct activator of adenylate cyclase. Because CREs are located in the promoter regions of the opioid peptide genes, preproenkephalin (PPE) and preprodynorphin (PPD), we investigated what effect continuous ICV infusion of H2O-soluble forskolin has on striatal PPE and PPD mRNA levels. Quantitative in situ hybridization histochemistry demonstrated that continuous activation of the adenylate cyclase/cAMP second messenger cascade results in a significant induction of striatal PPE and PPD mRNA at 6, 24, and 72 h. The sustained induction of striatal PPE and PPD mRNA indicates that pro-opioid gene transcription is not desensitized following 72 h of continuous adenylate cyclase activation. Continuous ICV infusion of 1, 9-dideoxyforskolin, a forskolin analog which does not activate adenylate cyclase, did not induce striatal PPE and PPD mRNA. These data are consistent with cAMP-dependent protein kinase-induced phosphorylation and binding of CREBs to CREs in the promoter regions of pro-opioid genes during sustained activation of adenylate cyclase.
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PMID:Forskolin induces preproenkephalin and preprodynorphin mRNA in rat striatum as demonstrated by in situ hybridization histochemistry. 778 55

The cAMP-dependent protein kinase (PKA) phosphorylates CREB327/341 at a single serine residue, Ser119/133, respectively. Phosphorylation at this site creates the sequence motif SXXXS(P), a consensus site of the glycogen synthase kinase-3 (GSK-3) enzyme (Fiol, C.J., Mahrenholz, A.M., Wang, Y., Roeske, R.W., and Roach, P.J. (1987) J. Biol. Chem. 262, 14042-14048). We examined the phosphorylation of CREB at the SXXXS(P) consensus site and its role in CREB transactivation to cAMP induction. Neither isoform of the GSK-3 enzyme (GSK-3 alpha or beta) utilizes CREB as its substrate unless CREB is already phosphorylated at Ser119/133. A 13-amino acid peptide containing the sequence surrounding Ser119/133 was phosphorylated by GSK-3, at Ser115/129, only after the primary phosphorylation of the peptide by PKA (at Ser119/133), suggesting that Ser115/129 is a GSK-3 phosphoacceptor site. Mutant CREB327/341 proteins containing Ser-->Ala substitutions confirmed Ser115/129 as the only GSK-3 phosphorylation site. Transfection assays of wild type and mutant Gal4-CREB fusion proteins in PC12 cells demonstrated that Ser-->Ala substitution of residue 129 of CREB341 impairs the transcriptional response to cAMP induction. Analogous mutation in CREB327 results in 70% decrease in its transactivation response to cAMP. In undifferentiated F9 cells, which are refractory to cAMP induction, transfected GSK-3 beta kinase induces a 60-fold increase in cyclic AMP response element-dependent transcription, mediated via the endogenous CREB protein. We propose that the hierarchical phosphorylation at the PKA and GSK-3 sites of CREB are essential for cAMP control of CREB.
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PMID:A secondary phosphorylation of CREB341 at Ser129 is required for the cAMP-mediated control of gene expression. A role for glycogen synthase kinase-3 in the control of gene expression. 779 17

Transcription factor CREB regulates cyclic AMP (cAMP)-dependent gene expression by binding to and activating transcription from cAMP response elements (CREs) in the promoters of target genes. The transcriptional transactivation functions of CREB are activated by its phosphorylation by cAMP-dependent protein kinase A (PKA). In studies of many different phenotypically distinct cells, the CRE of the somatostatin gene promoter is a prototype of a highly cAMP-responsive element regulated by CREB. We now report on a somatostatin-producing rat insulinoma cell line, RIN-1027-B2, in which transcription from the somatostatin gene promoter is paradoxically repressed by CREB. We find that CREB fails to transactivate a CRE-containing somatostatin-chloramphenicol acetyltransferase reporter even when coexpressed with the catalytic subunit of PKA. CAAT box/enhancer-binding protein beta (C/EBP beta) and C/EBP-related activating transcription factor bind to the CRE in the promoter of the somatostatin gene and transactivate transcription. CREB binds competitively with C/EBP beta to the somatostatin CRE in vitro and represses C/EBP beta-induced transcription of the CRE-containing somatostatin-chloramphenicol acetyltransferase reporter. The lack of CREB-mediated transcriptional stimulation is due to the presence of a heat-stable inhibitor of PKA that prevents activation of PKA and subsequent CREB phosphorylation in the nucleus. These findings indicate that dephosphorylated CREB is a negative regulator of C/EBP-activated transcription of the somatostatin gene promoter in RIN-1027-B2 cells.
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PMID:Impaired cyclic AMP-dependent phosphorylation renders CREB a repressor of C/EBP-induced transcription of the somatostatin gene in an insulinoma cell line. 779 50

Treatment of hamster cells in culture with the DNA alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) induces DNA polymerase beta (beta-pol) gene expression and cellular levels of the enzyme. Transcriptional activity of a cloned beta-pol promoter in transient expression assays is also stimulated. Among the requirements for these responses are methylation damage to genomic DNA, cellular cAMP-dependent protein kinase, and the ATF/CREB site of the cloned beta-pol promoter. In the present study, HeLa cell nuclear extract from MNNG-treated cells was much more active in an in vitro transcription assay than nuclear extract from normal cells. By using an oligonucleotide affinity column to deplete the nuclear extract of ATF/CREB, we showed that the difference was due to ATF/CREB activator. Purified ATF/CREB activator from MNNG-treated cells was approximately 10-fold more active than ATF/CREB purified from normal cells as a transcriptional activator for the depleted nuclear extract. ATF/CREB in the extract from normal cells is known to activate in vitro transcription by increasing the rate of promoter clearance [Narayan, S., Widen, S. G., Beard, W. A., & Wilson, S. H. (1994) J. Biol. Chem. 269, 12755-12763]. With ATF/CREB from MNNG-treated cells, the amount of preinitiation complex formed was much greater than with ATF/CREB from normal cells, and the kinetics of both the closed to open preinitiation complex isomerization and promoter clearance were altered. These results indicate that the mechanism of transcriptional activation secondary to DNA alkylation damage is recruitment of more preinitiation complex and alteration of the kinetic scheme of transcription initiation.
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PMID:DNA damage-induced transcriptional activation of a human DNA polymerase beta chimeric promoter: recruitment of preinitiation complex in vitro by ATF/CREB. 781 26

Cyclic AMP (cAMP) stimulates the expression of numerous genes through the protein kinase A (PK-A)-mediated phosphorylation of the nuclear factor CREB at Ser-133 (G. A. Gonzalez and M. R. Montminy, Cell 59:675-680, 1989). Like other signal transduction pathways, cAMP induces gene expression with burst-attenuation kinetics; cAMP-dependent transcription and CREB phosphorylation peak within 30 min and decline steadily over the next 4 to 6 h via the protein phosphatase 1-mediated dephosphorylation of CREB (M. Hagiwara, A. Alberts, P. Brindle, J. Meinkoth, J. Feramisco, T. Deng, M. Karin, S. Shenolikar, and M. Montminy, Cell 70:105-113, 1992). Here we characterize a third phase in cAMP-responsive transcription--a refractory period during which hormone-treated cells become transcriptionally unresponsive to subsequent stimulation by cAMP. This refractory period begins 6 to 8 h after stimulation and lasts 3 to 5 days after the removal of hormone. In contrast to the earlier attenuation phase, transcription of cAMP-responsive genes during the refractory period is not restored by inhibitors of protein phosphatase 1 activity. Rather, the establishment and maintenance of this phase rely on a marked reduction in PK-A catalytic subunit expression at the translational level. As overexpression of C-subunit protein can reactive transcription of cAMP-responsive genes during the refractory period, our results suggest that hormone-responsive cells may stimulate, attenuate, and then silence signal-dependent genes through distinct regulatory mechanisms.
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PMID:A refractory phase in cyclic AMP-responsive transcription requires down regulation of protein kinase A. 786 72


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