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At least 757 records · Page 42Linked to original sources
PubMed2004

CREB in the pond snail Lymnaea stagnalis: cloning, gene expression, and function in identifiable neurons of the central nervous system.

The pond snail Lymnaea stagnalis is an excellent model system in which to study the neuronal and molecular substrates of associative learning and its consolidation into long-term memory. Until now, the presence of cyclic AMP (cAMP)-responsive element binding protein (CREB), which is believed to be a necessary component in the process of a learned behavior that is consolidated into long-term memory, has only been assumed in Lymnaea neurons. We therefore cloned and analyzed the cDNA sequences of homologues of CREB1 and CREB2 and determined the presence of these mRNAs in identifiable neurons of the central nervous system (CNS) of L. stagnalis. The deduced amino acid sequence of Lymnaea CREB1 is homologous to transcriptional activators, mammalian CREB1 and Aplysia CREB1a, in the C-terminal DNA binding (bZIP) and phosphorylation domains, whereas the deduced amino acid sequence of Lymnaea CREB2 is homologous to transcriptional repressors, human CREB2, mouse activating transcription factor-4, and Aplysia CREB2 in the bZIP domain. In situ hybridization revealed that only a relatively few neurons showed strongly positive signals for Lymnaea CREB1 mRNA, whereas all the neurons in the CNS contained Lymnaea CREB2 mRNA. Using one of the neurons (the cerebral giant cell) containing Lymnaea CREB1 mRNA, we showed that the injection of a CRE oligonucleotide inhibited a cAMP-induced, long-lasting synaptic plasticity. We therefore conclude that CREBs are present in Lymnaea neurons and may function as necessary players in behavioral plasticity.

Amino Acid Sequence↗
PubMed2006

Differential effects of chronic amphetamine and baclofen administration on cAMP levels and phosphorylation of CREB in distinct brain regions of wild type and monoamine oxidase B-deficient mice.

Roles of GABA(B) transmission were explored in the action of amphetamine (Amph) on the brain. Adult male wild type (WT) and monoamine oxidase B-knocked out (MAOBKO) mice received i.p. injections of saline, d-Amph (5 mg/kg), plus baclofen (GABA(B) receptor agonist, 10 mg/kg), or baclofen and Amph, twice daily for 3 days and single treatments on day 4, followed by immuno-cyclic-AMP (cAMP) and immunoblotting assays on the brain tissue. The WT mice responded with higher levels of behavioral responses than the KO to the daily Amph injection; however, baclofen blocked the Amph-induced behavioral hyperactivity of both WT and KO mice. After the last treatment, levels of cAMP and phosphorylated (p) cyclic-AMP response element binding protein (CREB) were up-regulated in the striatum and somatosensory cortex of Amph-treated WT mice, while similar to the saline-controls in the baclofen+Amph-treated group, indicating the blockade by baclofen to Amph. Baclofen similarly suppressed the Amph-induced increases in pCREB levels of WT hippocampus and amygdala, and decreases of olfactory bulb and thalamus. For MAOBKO mice, baclofen hindered the Amph-generated increases in motor cortical cAMP and pCREB, and amygdaloid pCREB, and the decrease in olfactory bulb pCREB, whereas did not affect the Amph-raised hippocampal pCREB. Furthermore, the levels of CREB were variably modified in distinct regions by the drug exposures. The data reveal that the GABA(B)-mediated intracellular signaling differentially participates in mechanisms underlying Amph perturbation to various regions, and may thereby contribute explanations to the behavioral consequences. Moreover, MAOB is region-dependently involved in responses of the brain to Amph and baclofen, supporting interactions between GABA and monoamines.

Amphetamine↗
PubMed1999

Thrombin activates transcription factors sp1, NF-kappaB, and CREB: importance of the use of phosphatase inhibitors during nuclear protein extraction for the assessment of transcription factor DNA-binding activities.

Thrombin, a serine protease, is an important effector of many cellular processes and has been shown to up-regulate the expression of several genes. The mechanisms underlying thrombin-mediated regulation of gene transcription remain poorly understood. The original aim of this work was to study the effects of thrombin on the activation of transcription factors, Sp1, NF-kappaB, and CREB by means of electrophoretic mobility-shift assays (EMSA). However, an inconsistent pattern of results was observed. We raised the possibility that some EMSA results may have been erroneous by the fact that during the nuclear protein extraction and EMSA procedure, transcription factors are dephosphorylated by cellular phosphatases and hence their DNA-binding capacities are modified. Therefore, we have altered the original nuclear extraction protocol by including a mixture of phosphatase inhibitors during protein extraction and subsequent EMSA steps. We show here that this simple measure led to significant changes in both basal and thrombin-induced levels of activation of Sp1 and CREB, but not of NF-kappaB. In light of the data presented here, it would be important to reexamine the conclusions of many reports in which EMSA was used to assess the basal and agonist-induced levels of transcription factor DNA-binding activities.

Cells, Cultured↗
PubMed1999

Transcriptional activation of apurinic/apyrimidinic endonuclease (Ape, Ref-1) by oxidative stress requires CREB.

Apurinic/apyrimidinic endonuclease (APE alias Ref-1) is a multifunctional enzyme involved in DNA repair and redox regulation of transcription factors (e.g., AP-1). It also acts as a repressor of its own and other genes. Recently, it was shown that the level of APE mRNA and protein is enhanced upon treatment of cells with oxidative agents, such as hydrogen peroxide (H(2)O(2)), which gives rise to an adaptive response of cells to oxidative stress. Induction of APE is due to APE promoter activation. To elucidate the mechanism of transcriptional activation of APE by oxidative agents, we introduced mutations into the cloned human APE promoter and checked its activity in transient transfection assays. Here we demonstrate that mutational inactivation of a CREB binding site (CRE) present within the promoter completely abolished APE promoter activation by H(2)O(2), indicating that CREB is required for APE induction. The CRE element in the context of the APE promoter sequence binds c-Jun and ATF-2, which was shown in gel retardation experiments. Under conditions of induction of APE by H(2)O(2), the expression of c-Jun was significantly enhanced, which supports the view that induction of c-Jun is involved in signaling leading to APE promoter activation by oxidative stress.

Activating Transcription Factor 2↗
PubMed2000

Nucleoredoxin, glutaredoxin, and thioredoxin differentially regulate NF-kappaB, AP-1, and CREB activation in HEK293 cells.

Well-established mechanisms for regulation of protein activity include thiol-mediated oxidoreduction in addition to protein-protein interactions and phosphorylation. Nucleoredoxin (NRX), glutaredoxin (GRX), and thioredoxin (TRX) have been shown to act as a potent thiol reductase and reactive oxygen species regulator. They constitute a oxidoreductase superfamily and have been suggested as a candidate operating in the redox regulation of gene expression. We demonstrated here that intracellular localization of these redox molecules differ from each other and that the redox molecules differentially regulate NF-kappaB, AP-1, and CREB activation induced by TNFalpha, PMA, and forskolin and by expression of signaling intermediate kinases, NIK, MEKK, and PKA in HEK293 cells. This is a first report that describes involvement of NRX and GRX and differences from TRX in transcriptional regulation of NF-kappaB, AP-1, and CREB in living cells.

3T3 Cells↗
PubMed1995

A novel Creb family gene telomeric of HLA-DRA in the HLA complex.

cDNA selection was used to identify genes encoded by a 440-kb yeast artificial chromosome (YAC) clone that spanned from HLA-DRA to CYP21 in the HLA complex. An initially selected short cDNA was used to isolate a 2639-nucleotide, apparently full-length cDNA from a human tonsil library. This cDNA contained one extended open reading frame that predicted a protein of 700 amino acids with a basic region and a leucine zipper that is highly similar to members of the Creb/ATF subfamily. High-stringency Southern blotting of total human genomic DNA using this cDNA as the probe showed only a single locus that mapped to the selecting YAC clone. This gene, designated Creb-related protein (Creb-rp), is expressed ubiquitously and is evolutionarily conserved in mammals. It is located in the HLA Class III region 6-10 kb centromeric of the XB gene, which encodes a tenascin-like extracellular matrix protein. Homologous sequences are located in the Class II-Class III interval of the mouse H-2 complex. The amino acid sequence homology and general structural features of the predicted protein indicate that this gene encodes a general transcription factor belonging to the Creb/ATF subfamily of the bZip super-family.

Amino Acid Sequence↗
PubMed2002

Nicotinic regulation of CREB activation in hippocampal neurons by glutamatergic and nonglutamatergic pathways.

Activity-dependent gene expression is essential for form and function in the nervous system. Best understood is the role of glutamatergic signaling in controlling such events, but nicotinic signaling can also regulate transcription. We show here that nicotine can alter gene expression in rat hippocampal neurons, as reflected by activation of the transcription factor CREB and appearance of the immediate early gene product c-Fos. The process depends on both CaM and MAP kinases and on calcium release from internal stores. Part of the nicotinic effect is mediated via glutamatergic transmission, even in the absence of action potentials. Voltage-gated calcium channels are not necessary for nicotine-induced activation of CREB in hippocampal neurons. The low levels of sustained nicotinic stimulation required for transcriptional effects are consistent with those likely to be achievable either by the normal septal cholinergic innervation of the hippocampus or by repeated tobacco usage.

Acetylcholine↗
PubMed1996

Sequence requirements of ATF2 and CREB binding to the human T-cell leukemia virus type 1 LTR R region.

We have identified crucial transcription factor contact sites within the distal portion of the HTLV-1 LTR R region. Single base substitutions within this region greatly reduce formation of a complex which we previously described as a 70-kDa nuclear protein interacting with a CREB-like protein. Comparison of published sequences of HTLV-1 isolates obtained from scattered geographic locations revealed that clustered mutations in an 8-base segment near the U5 junction do, in fact, occur naturally. A single base substitution corresponding to a common naturally occurring mutation was introduced into the R region of an HTLV-1-LTR Cat construct. This resulted in derepression of the promoter in a cell line expressing high levels of the R region binding complex when compared to the wild-type LTR promoter. Affinity purification and electrophoretic mobility super-shift analysis identified a dominant 70-kDa DNA binding protein as ATF-2. Phosphorylated ATF-2 apparently interacts with CREB to form this downstream complex.

Activating Transcription Factor 2↗
PubMed2002

Comparison of CREB- and NF-kappaB-mediated transactivation by human T lymphotropic virus type II (HTLV-II) and type I (HTLV-I) tax proteins.

The function of the transactivator protein Tax from HTLV-II subtype A, subtype B, Brazilian subtype C, and African subtype D isolates was compared to that of Tax from an HTLV-I isolate. HTLV-II subtypes A, B, and C were less active in the transactivation of a NF-kappaB reporter compared to HTLV-I Tax in 293T but not Jurkat T cells. In both cell types there were no significant differences between the functions of HTLV-II B, C, and D and HTLV-I Tax proteins on either a full-length HTLV-I LTR or a 21-bp repeat reporter, suggesting that there is equivalent CREB-mediated transactivation between the viruses and these subtypes. In contrast, Tax of some but not all HTLV-II subtype A isolates, including the prototype Mo, had a greatly decreased ability to transactivate, and this could be directly correlated with a decrease in protein expression. Employment of cDNA clones encoding both Rex and Tax demonstrated that Rex was unable to rescue the expression or activity of the IIA Mo isolate. These studies demonstrate that with the exception of some HTLV-IIA subtypes there are no significant differences in Tax transactivation via the CREB and NF-kappaB pathways between the two viruses and suggest that the HTLV-II Tax may have a pathogenic potential equivalent to that of HTLV-I.

Amino Acid Sequence↗
PubMed2003

Regulation of human insulin gene transcription by the immunosuppressive drugs cyclosporin A and tacrolimus at concentrations that inhibit calcineurin activity and involving the transcription factor CREB.

Cyclosporin A and tacrolimus are important immunosuppressive drugs. They share a diabetogenic action as one of their most serious adverse effects. In a single study, tacrolimus (100 nM) inhibited human insulin gene transcription in the beta-cell line HIT. Using transfections of a human insulin-reporter gene into HIT cells, the present study shows that this inhibition is seen only at high concentrations of tacrolimus and is not caused by cyclosporin A. However, after stimulation by the major second messengers in the regulation of the insulin gene, cAMP and depolarization-induced calcium influx, both tacrolimus and cyclosporin A inhibited human insulin gene transcription in a concentration-dependent manner with IC(50) values of 1 nM and 30 nM, respectively. A further analysis offers a mechanism for this effect by revealing that the activation by cAMP and calcium of human insulin gene transcription is mediated by the transcription factor cAMP-responsive element binding protein (CREB) whose activity is inhibited by the immunosuppressants. These data demonstrate for the first time that cAMP- and calcium-induced activity of the human insulin gene is mediated by CREB and blocked by both tacrolimus and cyclosporin A at concentrations that inhibit calcineurin phosphatase activity. Since also the immunosuppressive effects of cyclosporin A and tacrolimus are thought to be secondary to inhibition of calcineurin, the present study suggests that inhibition of human insulin gene transcription by the immunosuppressants is clinically important and may contribute to their diabetogenic effect.

Calcineurin Inhibitors↗
PubMed2002

Molecular cloning and characterization of a novel human cAMP response element-binding ( CREB) gene ( CREB4).

Cyclic adenosine monophosphate (cAMP) response element-binding (CREB) proteins are a family of mammalian transcription activators. We identified a novel human CREB gene ( CREB4) that was 1592 bp long and encoded a protein of 395 amino acid residues. The protein shared high homology to mouse CREB3 (identity 62%, similarity 72%). The expression pattern of the human CREB4 gene showed transcripts in prostate, brain, pancreas, skeletal muscle, small intestine, testis, leukocyte, and thymus, whereas in heart, lung, liver, kidney, placenta, spleen, ovary, and colon, specific bands of the transcript could not be detected. The CREB4 gene consisted of ten exons and nine introns and was mapped to chromosome 1q21.3 by means of a bioinformatics analysis.

Amino Acid Sequence↗
PubMed1994

Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila.

Consolidated memory after olfactory learning in Drosophila consists of two components, a cycloheximide-sensitive, long-term memory (LTM) and a cycloheximide-insensitive, anesthesia-resistant memory (ARM). Using an inducible transgene that expresses a dominant negative member of the fly CREB family, LTM was specifically and completely blocked only after induction, while ARM and learning were unaffected. These results suggest that LTM formation requires de novo gene expression probably mediated by CREB family genes.

Amino Acid Sequence↗
PubMed1995

CREB as a memory modulator: induced expression of a dCREB2 activator isoform enhances long-term memory in Drosophila.

Genetic studies of memory formation in Drosophila have revealed that the formation of a protein synthesis-dependent long-term memory (LTM) requires multiple training sessions. LTM is blocked specifically by induced expression of a repressor isoform of the cAMP-responsive element-binding protein (CREB). Here, we report an enhancement of LTM formation after induced expression of an activator isoform of dCREB2. Maximum LTM is achieved after one training session, and its formation depends on phosphorylation of the activator transgene. A model of LTM formation based on differential regulation of CREB isoforms is proposed.

Animals↗
PubMed1990

Regulation of cAMP-inducible genes by CREB.

A large number of neuropeptides and neurotransmitters stimulate neuronal cells through the second messenger cAMP. These synaptic signals often cause profound changes in neuronal function by altering basic patterns of gene expression. Cyclic AMP, in turn, regulates a number of these genes through a conserved cAMP response element (CRE). Recently, a nuclear CRE-binding protein, CREB, has been shown to bind to the CRE and stimulate the transcription of cAMP-responsive genes. This article reviews recent progress towards understanding the mechanism by which cAMP modulates the activity of CREB to stimulate gene transcription.

Animals↗
PubMed1995

Carbon regulation of penicillin biosynthesis in Aspergillus nidulans: a minor effect of mutations in creB and creC.

Transcription of the Aspergillus nidulans ipnA gene is under carbon regulation. Loss-of-function mutations in creB or creC do not cause full derepression of ipnA transcript levels in sucrose-grown mycelia and do not elevate repressed penicillin levels, indicating that neither of these genes plays a major regulatory role in penicillin biosynthesis. However, these mutations reduce external pH acidification, accelerate sucrose degradation and result in extracellular accumulation of resulting D-glucose and D-fructose. These effects would explain the partial elevation of carbon-repressed ipnA transcript levels observed in strains carrying creB- or creC- mutations.

Aspergillus nidulans↗
PubMed2004

Involvement of CREB in the transcriptional regulation of the human GM3 synthase (hST3Gal V) gene during megakaryocytoid differentiation of human leukemia K562 cells.

We studied the transcriptional regulation of human GM3 synthase (hST3Gal V) during megakaryocytic differentiation of K562 cells induced by PMA. Northern blot and reverse transcription polymerase chain reaction (RT-PCR) indicated that the induction of hST3Gal V by phorbol 12-myristate 13-acetate (PMA) is regulated at transcriptional level. To elucidate the mechanism underlying the regulation of the hST3Gal V gene expression during the differentiation of K562 cells induced by PMA, we characterized the promoter region of the hST3Gal V gene. Functional analysis of the 5(')-flanking region of the hST3Gal V gene by transient expression method showed that the -177 to -83 region, which contains a CREB binding site at -143, functions as the PMA-inducible promoter in K562 cells. In addition, gel shift assay and site-directed mutagenesis indicated that the CREB binding site at -143 is crucial for the PMA-induced expression of the hST3Gal V in K562 cells.

Binding Sites↗
PubMed2006

Dual regulation of macrophage migration inhibitory factor (MIF) expression in hypoxia by CREB and HIF-1.

Macrophage migration inhibitory factor (MIF) is a well-described pro-inflammatory mediator that has also been implicated in the process of oncogenic transformation and tumor progression. However, despite the compelling evidence that MIF is overexpressed in, and contributes to, the pathology of inflammatory and malignant diseases the mechanisms that contribute to exaggerated expression of MIF have been poorly described. Here we show that hypoxia, and specifically HIF-1alpha, is a potent and rapid inducer of MIF expression. In addition, we demonstrate that hypoxia-induced MIF expression is dependent upon a HRE in the 5'UTR of the MIF gene but is further modulated by CREB expression. We propose a model where hypoxia-induced MIF expression is driven by HIF-1 but amplified by hypoxia-induced degradation of CREB. Given the importance of MIF in inflammatory and malignant diseases these data reveal a HIF-1-mediated pathway as a potential therapeutic target for suppression of MIF expression in hypoxic tissues.

5' Untranslated Regions↗
PubMed2004

The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector.

Elevations in circulating glucose and gut hormones during feeding promote pancreatic islet cell viability in part via the calcium- and cAMP-dependent activation of the transcription factor CREB. Here, we describe a signaling module that mediates the synergistic effects of these pathways on cellular gene expression by stimulating the dephosphorylation and nuclear entry of TORC2, a CREB coactivator. This module consists of the calcium-regulated phosphatase calcineurin and the Ser/Thr kinase SIK2, both of which associate with TORC2. Under resting conditions, TORC2 is sequestered in the cytoplasm via a phosphorylation-dependent interaction with 14-3-3 proteins. Triggering of the calcium and cAMP second messenger pathways by glucose and gut hormones disrupts TORC2:14-3-3 complexes via complementary effects on TORC2 dephosphorylation; calcium influx increases calcineurin activity, whereas cAMP inhibits SIK2 kinase activity. Our results illustrate how a phosphatase/kinase module connects two signaling pathways in response to nutrient and hormonal cues.

14-3-3 Proteins↗