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PubMed1998

Occurrence of a transcription factor, cAMP response element-binding protein (CREB), in the postsynaptic sites of the brain.

The postsynaptic density (PSD) fraction prepared from the rat forebrain contained a transcription factor, cAMP response element-binding protein (CREB). The occurrence of CREB in the PSD was confirmed by immunoelectron microscopic examination. CREB in the PSD fraction was phosphorylated both by protein kinase A and Ca2+/calmodulin-dependent protein kinase II (CaMKII) endogenous to the fraction, and dissociated from the PSD after phosphorylation, especially under CaMKII-activated conditions. The fraction containing CREB that was released from PSD after phosphorylation possessed cAMP response element (CRE)-binding activity. Thus, PSD anchors functionally active CREB. These results suggest that CREB anchored to the PSD is liberated by phosphorylation upon specific synaptic stimulation, translocates into the nucleus, and then triggers synaptic activity-dependent changes in gene expression.

Animals↗
PubMed2002

Predominant role by CaM kinase in NPY Y(1) receptor signaling: involvement of CREB [corrected].

The role of Ca(2+)/cAMP-dependent signal transduction and transcription factor CREB in mediating NPY- Y(1) receptor function was investigated in SK-N-MC cells. The Y(1) receptor agonist, [Leu(31),Pro(34)]-NPY, inhibited forskolin-stimulated cAMP production which was insensitive to thapsigargin or the CaM kinase II inhibitor, KN-93. Although activation of the Y(1) receptor leads to an increase in CREB phosphorylation, [Leu(31),Pro(34)]-NPY inhibited CREB phosphorylation in KN-93-treated cells. SK-N-MC cells were also transfected with PathDetect cis-CRE and trans-CREB/trans-cFos reporter genes to monitor the role of Ca(2+)/cAMP signals, triggered by Y(1) receptor, on reporter gene activity. Treatment of the cis-CRE-luciferase expression vector-transfected cells with [Leu(31),Pro(34)]-NPY increased reporter gene activity by 2 fold through a KN-93 sensitive pathway. In contrast, the peptide inhibited forskolin-stimulated luciferase activity. Consistently, [Leu(31),Pro(34)]-NPY induced trans-CREB mediated luciferase activity through a CaM kinase dependent pathway, and inhibited forskolin-stimulated luciferase gene expression. However, no effect of the peptide was observed on trans-cFos- mediated luciferase activity. These findings suggest that the NPY Y(1) receptor induces the expression of CRE containing target genes through the CaM kinase-CREB pathway, and inhibits CRE containing genes when cellular cAMP levels are elevated.

Benzylamines↗
PubMed2002

Phosphorylation of cAMP response element binding (CREB) protein during hypoxia in cerebral cortex of newborn piglets and the effect of nitric oxide synthase inhibition.

Previous studies have shown that hypoxia results in increased phosphorylation of CREB protein that mediates gene expression including that of the pro-apoptotic gene bax. We also have shown that hypoxia-induced expression of Bax protein is prevented by blocking nitric oxide synthase (NOS). The present study tests the hypothesis that inhibition of NOS by N-nitro-L-arginine (NNLA) will prevent the hypoxia-induced increased phosphorylation of CREB protein in neuronal nuclei of newborn piglets. To test this hypothesis, phosphorylation of CREB protein was assessed by immunoblotting neuronal nuclear proteins from five normoxic (Nx), 10 hypoxic (Hx) and five Hx-NNLA-treated 3-5-day-old piglets. NNLA (40 mg/kg) or saline was infused over 60 min prior to induction of hypoxia. Hypoxia was achieved by reducing the FiO(2) (0.15 to 0.05) for 60 min and documented biochemically by ATP and phosphocreatine (PCr) levels. Neuronal nuclei were isolated using discontinuous sucrose gradient centrifugation and purified. Nuclear proteins were separated on 12% sodium dodecylsulfate-polyacrylamide gel electrophoresis, transferred to nitrocellulose membranes, reacted with anti-phosphorylated CREB protein antibody and conjugated with horseradish peroxidase antibody. Protein bands were detected using the enhanced chemiluminescence method and quantitated by imaging densitometry. Protein density was expressed as absorbance (OD)xmm(2). ATP levels (micromol/g brain) were 4.3+/-0.6 in the Nx group, 1.3+/-0.5 in the Hx group (P<0.001) and 1.1+/-0.2 in the Hx-NNLA group (P<0.001 vs. Nx and Hx). Similarly, PCr levels (micromol/g brain) were 3.8+/-0.6 in the Nx group, 0.7+/-0.2 in the Hx group (P<0.001) and 0.6+/-0.1 in the Hx-NNLA group (P<0.001 vs. Nx and Hx). Density of phosphorylated CREB protein (ODxmm(2)) was 134.2+/-52.4 in the Nx group compared to 746.0+/-76.8 in the Hx group (P<0.05) and 491.1+/-40.9 in the Hx-NNLA group (P<0.05 Hx). The data show that NOS inhibition attenuates the hypoxia-induced increase in CREB protein phosphorylation in the cerebral cortex of newborn piglets.

Adenosine Triphosphate↗
PubMed1992

Mapping Creb-1 to chromosome 1 in the mouse.

The gene CREB1 encoding the cyclic AMP response element DNA binding protein was previously assigned to human 2q32.3-q34. In this study, a panel of 207 backcross mice made between C57BL/10ScSn (=B10) females and (B10 x B10.L-Lsh)F1 males were used to map Creb-1 with respect to Cryg and Lsh/Vil on mouse chromosome 1. A reverse-transcribed, polymerase chain reaction-amplified cDNA probe covering bp 39 to 554 of the human sequence identified restriction fragment length polymorphisms with 7/18 restriction endonucleases used to digest whole genomic mouse DNA from the parental strains. BglII and DraI RFLPs for Creb-1 were scored on a subpanel of 16/207 known recombinants between Cryg and Lsh/Vil, yielding 2/16 recombinants between Cryg and Creb-1 and 14/16 recombinants between Creb-1 and Lsh/Vil. The 16/207 recombinants observed between Lsh/Vil and Cryg provide an estimated recombination frequency of 0.077 +/- 0.019, equivalent to a map distance of 7.7 +/- 1.9 cM. This is in good agreement with previously published map distances. The number of recombinants observed between Creb-1 and the other markers place Creb-1 approximately 1 cM distal to Cryg and 7 cM proximal to Lsh/Vil.

Animals↗
PubMed1996

Signaling from synapse to nucleus: postsynaptic CREB phosphorylation during multiple forms of hippocampal synaptic plasticity.

Phosphorylation of the transcription factor CREB is thought to be important in processes underlying long-term memory. It is unclear whether CREB phosphorylation can carry information about the sign of changes in synaptic strength, whether CREB pathways are equally activated in neurons receiving or providing synaptic input, or how synapse-to-nucleus communication is mediated. We found that Ca(2+)-dependent nuclear CREB phosphorylation was rapidly evoked by synaptic stimuli including, but not limited to, those that induced potentiation and depression of synaptic strength. In striking contrast, high frequency action potential firing alone failed to trigger CREB phosphorylation. Activation of a submembranous Ca2+ sensor, just beneath sites of Ca2+ entry, appears critical for triggering nuclear CREB phosphorylation via calmodulin and a Ca2+/calmodulin-dependent protein kinase.

Action Potentials↗
PubMed2002

Apoptosis, axonal growth defects, and degeneration of peripheral neurons in mice lacking CREB.

CRE-binding protein (CREB) belongs to a family of transcription factors that mediates stimulus-dependent gene expression in neuronal and non-neuronal cells. Here we show that CREB is phosphorylated on its transcriptional regulatory site, Ser-133, in vivo in a neurotrophin-dependent manner. In mice harboring a null mutation in the Creb gene, sensory neurons exhibit excess apoptosis and degeneration, and display impaired axonal growth and projections. Interestingly, excess apoptosis is not observed in the central nervous system. CREB is required within sensory and sympathetic neurons for survival and axon extension since both of these neurotrophin-dependent processes are compromised in cultured neurons from CREB null mice. Thus, during their period of neurotrophin dependency, peripheral neurons require CREB-mediated gene expression for both survival and growth in vivo.

Animals↗
PubMed2002

Modulation of CREB activity by the Rho GTPase regulates cell and organism size during mouse embryonic development.

Rho GTPases regulate several aspects of tissue morphogenesis during animal development. We found that mice lacking the Rho-inhibitory protein, p190-B RhoGAP, are 30% reduced in size and exhibit developmental defects strikingly similar to those seen in mice lacking the CREB transcription factor. In p190-B RhoGAP-deficient mice, CREB phosphorylation is substantially reduced in embryonic tissues. Embryo-derived cells contain abnormally high levels of active Rho protein, are reduced in size, and exhibit defects in CREB activation upon exposure to insulin or IGF-1. The cell size defect is rescued by expression of constitutively activated CREB, and in wild-type cells, expression of activated Rho or dominant-negative CREB results in reduced cell size. Together, these results suggest that activity of the Rho GTPase modulates a signal from insulin/IGFs to CREB that determines cell size and animal size during embryogenesis.

Animals↗
PubMed2003

Role of CRE-binding protein (CREB) in aromatase expression in breast adipose.

Estrogen biosynthesis from C19 steroids is catalyzed by aromatase cytochrome P450. Aromatase is expressed in breast adipose tissue through the use of a distal, cytokine-responsive promoter (promoter I.4). Breast tumors, however, secrete soluble factors that over-stimulate aromatase expression through an alternative proximal cAMP-responsive promoter, promoter II. We have mapped the cAMP-responsive regions of promoter II by transient transfection of 3T3-L1 preadipocytes with aromatase promoter II reporter genes. 5' deletion and mutation analyses identified two cAMP response element (CRE)-like sequences (CRE1 and CRE2) that were essential for cAMP-induced promoter II activity. Electrophoretic mobility shift analysis demonstrated that CRE binding protein (CREB) bound to each element, and that this interaction was enhanced in the presence of cAMP. Quantification of CREB mRNA expression in adipose tissue from normal and tumor bearing breast adipose tissue revealed that CREB expression is approximately five times higher in tumor bearing than in normal breast adipose tissue. Thus, the over expression of aromatase in adipose tissue surrounding breast tumors could arise through increases in both CREB expression and CREB transcriptional activity. Pharmacological inhibition of CREB activity, previously shown to have anti-proliferative effects on cancer cells, might therefore have additional benefits through inhibition of aromatase expression and thus estrogen production in breast adipose.

Adipose Tissue↗
PubMed2001

CREB regulates hepatic gluconeogenesis through the coactivator PGC-1.

When mammals fast, glucose homeostasis is achieved by triggering expression of gluconeogenic genes in response to glucagon and glucocorticoids. The pathways act synergistically to induce gluconeogenesis (glucose synthesis), although the underlying mechanism has not been determined. Here we show that mice carrying a targeted disruption of the cyclic AMP (cAMP) response element binding (CREB) protein gene, or overexpressing a dominant-negative CREB inhibitor, exhibit fasting hypoglycaemia [corrected] and reduced expression of gluconeogenic enzymes. CREB was found to induce expression of the gluconeogenic programme through the nuclear receptor coactivator PGC-1, which is shown here to be a direct target for CREB regulation in vivo. Overexpression of PGC-1 in CREB-deficient mice restored glucose homeostasis and rescued expression of gluconeogenic genes. In transient assays, PGC-1 potentiated glucocorticoid induction of the gene for phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme in gluconeogenesis. PGC-1 promotes cooperativity between cyclic AMP and glucocorticoid signalling pathways during hepatic gluconeogenesis. Fasting hyperglycaemia is strongly correlated with type II diabetes, so our results suggest that the activation of PGC-1 by CREB in liver contributes importantly to the pathogenesis of this disease.

Adenoviridae↗
PubMed1996

Defective thymocyte proliferation and IL-2 production in transgenic mice expressing a dominant-negative form of CREB.

The basic/leucine zipper (bZip) transcription factor, CREB, binds to the CRE element (TGANNTCA). The transcriptional activity of CREB requires phosphorylation of the protein on a serine residue at position 119 (ref. 6). CREs are present in a number of T-cell genes but the precise role of CREB in T-cell differentiation and function was unknown. Here we show that resting thymocytes contain predominantly unphosphorylated (inactive) CREB, which is rapidly activated by phosphorylation on Ser 119 following thymocyte activation. T-cell development is normal in transgenic mice that express a dominant-negative form of CREB (CREBA119, with alanine at position 119) under the control of the T-cell-specific CD2 promoter/enhancer. In contrast, thymocytes and T cells from these animals display a profound proliferative defect characterized by markedly decreased interleukin-2 production, G1 cell-cycle arrest and subsequent apoptotic death in response to a number of different activation signals. This proliferative defect is associated with the markedly reduced induction of c-jun, c-fos, Fra-2 and FosB following activation of the CREBA119 transgenic thymocytes. We propose that T-cell activation leads to the phosphorylation and activation of CREB, which in turn is required for normal induction of the transcription factor AP1 and subsequent interleukin-2 production and cell-cycle progression.

Activating Transcription Factors↗
PubMed2006

Regulation of osteoclast differentiation and function by the CaMK-CREB pathway.

Calcium (Ca(2+)) signaling is essential for a variety of cellular responses and higher biological functions. Ca(2+)/calmodulin-dependent kinases (CaMKs) and the phosphatase calcineurin activate distinct downstream pathways that are mediated by the transcription factors cAMP response element (CRE)-binding protein (CREB) and nuclear factor of activated T cells (NFAT), respectively. The importance of the calcineurin-NFAT pathway in bone metabolism has been demonstrated in osteoclasts, osteoblasts and chondrocytes. However, the contribution of the CaMK-CREB pathway is poorly understood, partly because of the difficulty of dissecting the functions of homologous family members. Here we show that the CaMKIV-CREB pathway is crucial for osteoclast differentiation and function. Pharmacological inhibition of CaMKs as well as the genetic ablation of Camk4 reduced CREB phosphorylation and downregulated the expression of c-Fos, which is required for the induction of NFATc1 (the master transcription factor for osteoclastogenesis) that is activated by receptor activator of NF-kappaB ligand (RANKL). Furthermore, CREB together with NFATc1 induced the expression of specific genes expressed by differentiated osteoclasts. Thus, the CaMK-CREB pathway biphasically functions to regulate the transcriptional program of osteoclastic bone resorption, by not only enhancing induction of NFATc1 but also facilitating NFATc1-dependent gene regulation once its expression is induced. This provides a molecular basis for a new therapeutic strategy for bone diseases.

Animals↗
PubMed2003

Ohmefentanyl stereoisomers induce changes of CREB phosphorylation in hippocampus of mice in conditioned place preference paradigm.

The present study was designed to determine the changes of phosphorylation of cAMP- response element binding protein (CREB) in hippocampus induced by ohmefentanyl stereoisomers (F9202 and F9204) in conditioned place preference (CPP) paradigm. The results showed that mice receiving F9202 and F9204 displayed obvious CPP. They could all significantly stimulate CREB phosphorylation and maintained for a long time without affecting total CREB protein levels. The effect of F9204 was similar to morphine which effect was more potent and longer than F9202. We also examined the effects of ketamine, a noncompetitive N-mthyl-D-aspartate receptor (NR) antagonist, on morphine-, F9202- and F9204- induced CPP and phosphorylation of CREB in hippocampus. Ketamine could suppress not only the place preference but also the phosphorylation of CREB produced by morphine, F9202 and F9204. These findings suggest that alterations in the phosphorylation of CREB be relevant to opiates signaling and the development of opiates dependence. NR antagonists may interfere with opiates dependence and may have potential therapeutic implications.

Analgesics↗
PubMed2001

Fear memory retrieval induces CREB phosphorylation and Fos expression within the amygdala.

Fear memory retrieval has been shown to induce a protein-synthesis dependent re-consolidation of memories within the amygdala. Here, using immunocytochemistry, we investigated the molecular basis of this process in the rat and show that retrieval of a cued fear memory induces the activation, by phosphorylation, of the transcription factor CREB within the basal and lateral nuclei of the amygdala, as well as expression of the CREB-regulated immediate-early gene, c-fos, in the basal amygdala. We also show an increase in CREB phosphorylation within the central nucleus of the amygdala following behavioural testing, with an accompanying increase in Fos-immunoreactive nuclei in animals retrieving the cued association. There were no changes in either phosphorylated CREB or Fos in the hippocampus following exposure to discrete fear stimuli. These results show that activation of CREB, which has been shown to be involved in the formation of long-term fear memories, also accompanies memory retrieval, and also suggest a role for CREB phosphorylation in memory re-consolidation following retrieval.

Amygdala↗
PubMed1998

CD2 signalling induces phosphorylation of CREB in primary lymphocytes.

Promoter sequences responsive to cyclic AMP (cAMP) are found in a number of cellular genes, and bind transcription factors of the cAMP response element binding protein (CREB)/activating transcription factor-1 (ATF-1) family. We have used a human T-lymphotropic virus type 1 (HTLV-1) model of cAMP response element (CRE) transcription to investigate the influence of lymphocyte activation on transcription from homologous regions in the viral promoter. We previously demonstrated increased HTLV-1 transcription following CD2 but not CD3 receptor cross-linking. We hypothesized that this increased viral transcription was mediated, in part, through the phosphorylation of CREB. Therefore, we investigated CD2 and CD3 receptor-mediated signalling in primary human peripheral blood mononuclear cells (PBMC). CD2, but not CD3, cross-linking increased cAMP detected by competitive enzyme-linked immunosorbent assay (ELISA) approximately fourfold. CD2 cross-linking concurrently increased phosphorylation of CREB detected by immunoblot assay eightfold. Consistent with post-translational regulation, no change in total level of CREB protein was observed. Phosphorylation of CREB occurred through a herbimycin A and Rp-cAMP-sensitive pathway, suggesting phosphorylation required antecedent activation of both protein tyrosine kinases (PTK) and protein kinase A (PKA). Both CD2 and CD3 cross-linking increased binding of nuclear proteins to a radiolabelled CRE oligonucleotide probe in electrophoretic mobility shift assays suggesting that lymphocyte activation enhances binding independently of phosphorylation of CREB at serine 133. These data indicate specific modulation of the CREB/ATF-1 family of transcription factors by the CD2 signalling pathway and suggest CD2 receptor modulation of CRE-mediated transcription following ligand engagement (e.g. cell-to-cell contact).

Activating Transcription Factor 2↗
PubMed2002

The WD40-repeat protein CreC interacts with and stabilizes the deubiquitinating enzyme CreB in vivo in Aspergillus nidulans.

Genetic dissection of carbon catabolite repression in Aspergillus nidulans has identified two genes, creB and creC, which, when mutated, affect expression of many genes in both carbon catabolite repressing and derepressing conditions. The creB gene encodes a functional deubiquitinating enzyme and the creC gene encodes a protein that contains five WD40 repeat motifs, and a proline-rich region. These findings have allowed the in vivo molecular analysis of a cellular switch involving deubiquitination. We demonstrate that overexpression of the CreB deubiquitinating enzyme can partially compensate for a lack of the CreC WD40-repeat protein in the cell, but not vice versa and, thus, the CreB deubiquitinating enzyme acts downstream of the CreC WD40-repeat protein. We demonstrate using co-immunoprecipitation experiments that the CreB deubiquitinating enzyme and the CreC WD40-repeat protein interact in vivo in both carbon catabolite repressing and carbon catabolite derepressing conditions. Further, we show that the CreC WD40-repeat protein is required to prevent the proteolysis of the CreB deubiquitinating enzyme in the absence of carbon catabolite repression. This is the first case in which a regulatory deubiquitinating enzyme has been shown to interact with another protein that is required for the stability of the deubiquitinating enzyme.

Aspergillus nidulans↗
PubMed1996

Transcriptional regulation of CREB (cyclic AMP response element-binding protein) expression in CATH.a cells.

We have recently demonstrated that mRNA expression of cyclic AMP (cAMP) response element-binding protein (CREB) is down-regulated in CATH.a cells (a neural-derived cell line) by activation of the cAMP pathway. We now demonstrate that this down-regulation can be accounted for by a decrease in the rate of CREB gene transcription. It was found that cycloheximide, a protein synthesis inhibitor, prevented the forskolin-induced decrease in CREB mRNA levels in CATH.a cells. Nuclear run-on assays demonstrated that forskolin decreased the rate of CREB transcription by close to 50%. Moreover, forskolin decreased chloramphenicol acetyltransferase (CAT) activity in CATH.a cells transiently transfected with a construct containing 1,240 bp of CREB promoter fused to a CAT reporter plasmid. Possible mechanisms by which activation of the cAMP pathway leads to a decrease in CREB gene transcription are discussed.

Animals↗
PubMed2001

The transcription factors CREB and c-Fos play key roles in NCAM-mediated neuritogenesis in PC12-E2 cells.

The neural cell adhesion molecule (NCAM) stimulates axonal outgrowth by activation of the Ras-mitogen activated protein kinase (MAPK) pathway and by generation of arachidonic acid. We investigated whether the transcription factors, cyclic-AMP response-element binding protein (CREB) and c-Fos play roles in this process by estimating NCAM-dependent neurite outgrowth from PC12-E2 cells grown in co-culture with NCAM-negative or NCAM-positive fibroblasts. PC12-E2 cells were transiently transfected with expression plasmids encoding wild-type or dominant negative forms of CREB and c-Fos or an activated form of the MAPK kinase, MEK2. Alternatively, PC12-E2 cells were treated with arachidonic acid, the cAMP analogue dBcAMP, or protein kinase A (PKA) inhibitors. The negative forms of CREB and c-Fos inhibited neurite outgrowth mediated by NCAM, arachidonic acid, dBcAMP, or MEK2. Neither CREB nor c-Fos could compensate for the inactivation of the other, indicating that both factors are important in NCAM-mediated neuritogenesis. Treatment of primary hippocampal neurons with a synthetic NCAM peptide ligand known to stimulate neurite outgrowth induced phosphorylation of CREB and expression of c-fos. We thus present evidence that NCAM-mediated neurite outgrowth involves a series of signal transduction pathways, including the cAMP/PKA pathway, targeting c-Fos and CREB.

Animals↗
PubMed2001

The left ventricular stress-velocity relation in transgenic mice expressing a dominant negative CREB transgene in the heart.

OBJECTIVE: CREB(A133) transgenic mice that express a dominant negative CREB transcription factor in cardiomyocytes develop a dilated cardiomyopathy that is anatomically, physiologically, and clinically similar to human idiopathic dilated cardiomyopathy. The goals of this study were to quantitate left ventricular (LV) contractility and measure cardiac reserve in CREB(A133) mice by using the relation of end-systolic wall stress to the velocity of fiber shortening. METHODS: A total of 37 adult CD-1 mice (including both nontransgenic and CREB(A133) transgenic mice) were studied with simultaneously acquired high-fidelity instantaneous aortic pressures and 2-dimensionally targeted M-mode echocardiograms. RESULTS: CREB(A133) mice displayed significantly lower values of LV fiber shortening velocities over a wide range of afterloads, and they displayed smaller dobutamine-induced shifts from baseline contractility relations. Counterbalancing effects of differences in LV geometry and aortic pressures resulted in comparable levels of LV wall stress during ejection in both groups. CONCLUSION: These results demonstrate directly that CREB(A133) mice display reduced LV contractility at baseline and decreased cardiac reserve.

Animals↗