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At least 451 records · Page 25Linked to original sources
PubMed2006

A critical role of CREB in the impairment of late-phase LTP by adult onset hypothyroidism.

We have shown previously that adult onset hypothyroidism impairs late-phase long-term potentiation (L-LTP) and reduces the protein levels of mitogen-activated protein kinases (MAPKp44/42 (ERK1/2)) in area CA1 of the hippocampus. In the present study, basal and stimulated levels of signaling molecules essential for the expression of L-LTP were determined in area CA1 of the hippocampus. L-LTP was evoked by multiple train high-frequency stimulation (MHFS) in area CA1 of the hippocampus of thyroidectomized and sham control anesthetized adult rats. Immunoblot analysis showed reduction in the basal protein levels of adenylyl cyclase I (ACI), calcium calmodulin-dependent protein kinase IV (CaMKIV), and cyclic-AMP response element-binding protein (CREB; phosphorylated (P-) and total) in hypothyroid rats. A significant increase in the levels of P-CREB, P-MAPKp44 and P-MAPKp42 was seen 4 h after MHFS in sham-operated control animals, but not in hypothyroid animals. The levels of total CREB, total MAPKp44, total MAPKp42 and CaMKIV were elevated in both groups 4 h after MHFS. Our results suggest that in adult hypothyroid rats, the reduced basal level of CaMKIV, MAPKp44/42 and CREB along with the failure of MHFS to induce MAPKp44/42 and CREB phosphorylation may be responsible for L-LTP impairment in the CA1 area during hypothyroidism.

Adenylyl Cyclases↗
PubMed2005

Traditional Chinese medicine Bao Gan Ning increase phosphorylation of CREB in liver fibrosis in vivo and in vitro.

Previous studies have demonstrated that traditional Chinese medicine Bao Gan Ning, which contains six different drugs: Trionyx sinensis Wiegmann shell, Prunus persica (L.) Batsch seed, Salvia miltiorrhiza Bge. root, Mallotus opelta (Lour.) Muell-Arg root, Astragalus membranaceus (Fisch.) Bge. var. mongho-licus (Bge.) Hsiao root and Scutellaria baicalensis Georgi root, was able to protect liver against fibrosis in CCL4 models. In an effort to elucidate molecular mechanisms by which Bao Gan Ning exerts its anti-fibrosis activity, effects of Bao Gan Ning on liver fibrosis and cAMP response element binding protein (CREB), an important transcription factor involved in liver fibrosis, were evaluated in animal and cell models in this work. Results showed that Bao Gan Ning (2.16 or 4.32 g/kg/day) significantly decreased alanine aminotransferase (ALT) and hyaluronidase levels and reversed liver fibrosis in rat liver fibrosis models. The proliferation of HSC-T6, a hepatic stellate cell line, was also significantly inhibited by incubation with serums that were prepared from rats fed with Bao Gan Ning. Most interestingly, results from Western blot, immunohistochemistry and electrophoretic mobility shift assay (EMSA) showed that Bao Gan Ning up-regulated CREB phosphorylation both in rat liver fibrosis models and in HSC-T6 cells, but did not affect protein level of CREB and the DNA binding activity of CREB. These results suggested that up-regulation of CREB phosphorylation may be involved in anti-fibrosis activity of Chinese medicine Bao Gan Ning.

Animals↗
PubMed2005

Dominant negative FTase (DNFTalpha) inhibits ERK5, MEF2C and CREB activation in adipogenesis.

We recently demonstrated that dominant negative FTase/GGTase I alpha-subunit-inhibited (DNFTalpha-inhibited) insulin-stimulated adipocytes differentiation. DNFTalpha interferes with Ras prenylation whereby ERK1/2, CREB and the differentiation cascade are downregulated. To further investigate prenylation in adipogenesis, we examined DNFTalpha's ability to inhibit activation of ERK5, MEF2C and CREB. DNFTalpha-inhibited insulin-stimulated expression, activation and nuclear translocation of ERK5. Inhibition was associated with decreased activation of MEF2C and CREB by 80 and 78%, respectively. PD98059 did not block activation of ERK5 and MEF2C, but inhibited CREB phosphorylation by 90%. ERK5 siRNA-inhibited MEF2C activation, whereas it reduced CREB phosphorylation only 50%. Pre-adipocytes expressing DNFTalpha or treated with PD98059 were unable to differentiate to mature adipocytes, whereas pre-adipocytes transfected with ERK5 siRNA showed moderate inhibition of insulin-induced adipogenesis. Taken together, these data suggest that prenylation plays a critical role in insulin-stimulated adipogenesis, and that the ERK5 plays an important, but less crucial role in adipogenesis as compared to ERK1/2.

3T3-L1 Cells↗
PubMed2004

Inducible repression of CREB function disrupts amygdala-dependent memory.

Evidence from Aplysia, Drosophila, mice, and rats indicates that the CREB (cAMP/Ca2+ responsive element binding protein) family of transcription factors is critical for long-term memory. Recent findings, however, suggest that performance abnormalities may contribute to the memory deficits attributed to CREB manipulations in mammals. To clarify the role of CREB in memory, we used a paradigm, conditioned taste avoidance, that places few performance demands on the subject. We show that lesioning or blocking protein synthesis in the basolateral amygdala of mice disrupts conditioned taste aversion. Furthermore, either chronically or acutely disrupting CREB function in two different types of genetically modified mice blocks memory for conditioned taste aversion measured 24 h following training. Together, these findings indicate that CREB-mediated transcription and protein synthesis are required for conditioned taste aversion memory.

Amygdala↗
PubMed2006

Phosphorylation state of CREB in the rat hippocampus: a molecular switch between spatial novelty and spatial familiarity?

The activation of cAMP response element-binding protein (CREB) after a learning experience is a common feature in the formation of several associative memories. We recently demonstrated that the increase in the hippocampal phosphorylated CREB (pCREB) levels 1 h after a short exploration of an open field (OF) was associated to detection of spatial novelty and was not related to the memory formation of habituation in this non-associative learning paradigm. Moreover, after a long training of three OF sessions, hippocampal pCREB levels were below to that observed in control rats. The present results show that such decrease does not correlate with memory retrieval or improvement in long-term memory of habituation. Instead, it is associated with the familiarity to the arena. Our experiments revealed that the relevant variable to induce CREB deactivation was the prolonged exploration of the arena (30 min). A 15 min OF exploration was ineffective. Furthermore, the last 5 min period of a prolonged exploration was crucial to change CREB phosphorylation state: when exploration took place in a novel arena the level of pCREB increased; in contrast, when it was performed in the familiar OF, pCREB levels decreased. Taken as a whole, our results suggest that CREB phosphorylation state in the hippocampus switches in response to exposure to a novel or to a familiar spatial environment.

Animals↗
PubMed2003

SP600125, an inhibitor of c-jun N-terminal kinase, activates CREB by a p38 MAPK-mediated pathway.

SP600125, an anthrapyrazolone inhibitor of c-jun N-terminal kinase (JNK), has been used to characterize the role of JNK in apoptotic pathways. In this study, we have demonstrated an additional novel anti-apoptotic action of this inhibitor in MIN6 cells, a mouse beta cell line. SP600125 induced CREB-dependent promoter activation by 2.8-fold at 20 microM, the concentration at which it inhibited c-jun-dependent promoter activation by 51%. There was a significant (P<0.01) increase in CREB phosphorylation (serine 133) at 5 min, which persisted for a period of 2h. Examination of signaling pathways upstream of CREB showed a 2.5-fold increase in the active phospho form of p38 MAPK. This finding was further confirmed by an in vitro kinase assay using ATF-2 as substrate. SB203580, an inhibitor of p38 MAPK, partially blocked SP600125-mediated activation of CREB. These observations suggest that SP600125 could be used as a small molecular weight activator of CREB.

Animals↗
PubMed2001

The cAMP response element binding protein-2 (CREB-2) can interact with the C/EBP-homologous protein (CHOP).

cAMP response element binding protein-2 (CREB-2) is a basic leucine zipper (bZIP) factor that was originally described as a repressor of CRE-dependent transcription but that can also act as a transcriptional activator. Moreover, CREB-2 is able to function in association with the viral Tax protein as an activator of the human T-cell leukemia virus type I (HTLV-I) promoter. Here we show that CREB-2 is able to interact with C/EBP-homologous protein (CHOP), a bZIP transcription factor known to inhibit CAAT/enhancer-dependent transcription. Cotransfection of CHOP with CREB-2 results in decreased activation driven by the cellular CRE motif or the HTLV-I proximal Tax-responsive element, confirming that CREB-2 and CHOP can interact with each other in vivo.

Activating Transcription Factor 4↗
PubMed2001

Environmental enrichment: effects on spatial memory and hippocampal CREB immunoreactivity.

Environmental enrichment has been shown to improve performance in tests of spatial memory, induce neurogenesis in the hippocampus, enhance survival of newly formed granule cells, and inhibit spontaneous apoptosis. Although neuroplasticity of the mammalian brain declines with age, recent evidence suggests that the adult brain exhibits significant plasticity in response to environmental stimulation. The present study was designed to evaluate the effect of environmental enrichment on spatial memory and on immunoreactivity to cAMP response element binding protein (CREB) from the hippocampus. C57/BL/6 mice were trained in a Morris water maze after exposure to an enriched environment, either from 35 to 94 days or from 100 to 159 days of age. Hippocampal tissue from representative animals was later analyzed by Western blot for CREB immunoreactivity. Results indicate that environmental enrichment (particularly during the earlier period) improved performance on the Morris water maze and tended to increase immunoreactivity to CREB in the hippocampus. Social interaction by itself did not result in significant differences in navigational performance. Results with regard to social interaction and CREB immunoreactivity were mixed. Results are discussed in terms of evaluating the construct of enrichment, the correlation of CREB transcription and behavior change, and the importance of the developmental period for enrichment.

Animals↗
PubMed2003

Regulation of T cell activation by HIV-1 accessory proteins: Vpr acts via distinct mechanisms to cooperate with Nef in NFAT-directed gene expression and to promote transactivation by CREB.

Nef and Vpr are lentiviral accessory proteins that have been implicated in regulation of cellular gene expression. We noticed that Vpr can potentiate Nef-induced activation of nuclear factor of activated T cells (NFAT)-dependent transcription. Unlike Nef, which stimulated calcium signaling to activate NFAT, Vpr functioned farther downstream. Similar to the positive effects of Vpr on most of the transcriptional test systems that we used, potentiation of NFAT-directed gene expression was relatively modest in magnitude (two- to threefold) and depended on the cell cycle-arresting capacity of Vpr. By contrast, we found that Vpr could cause more than fivefold upregulation of cyclic AMP response element (CRE)-directed transcription via a mechanism that did not require Vpr-induced G2/M arrest. This effect, however, was only evident under suboptimal conditions known to lead to serine phosphorylation of the CRE binding factor (CREB) but not to CREB-dependent gene expression. This suggested that Vpr may act by stabilizing interactions with CREB and its transcriptional cofactor CREB binding protein (CBP). Indeed, this effect could be blocked by cotransfection of the adenoviral CBP inhibitor E1A. These results provide additional evidence for cell cycle-independent regulation of gene expression by Vpr and implicate CREB as a potentially important target for Vpr action in HIV-infected host cells.

Cyclic AMP Response Element-Binding Protein↗
PubMed2002

Mechanisms of basal and kinase-inducible transcription activation by CREB.

The cAMP response element (CRE)-binding protein (CREB) stimulates basal transcription of CRE-containing genes and mediates induction of transcription upon phosphorylation by protein kinases. The basal activity of CREB maps to a carboxy-terminal constitutive activation domain (CAD), whereas phosphorylation and inducibility map to a central, kinase-inducible domain (KID). The CAD interacts with and recruits the promoter recognition factor TFIID through an interaction with a specific TATA-binding-protein-associated factor (TAF), dTAFII110/ hTAFII135. Interaction between the TAF and the CAD is mediated by a central cluster of hydrophobic amino acids, mutation of which disrupts TAF binding, polymerase recruitment, and transcription activation. Assessment of the contributions of the CAD and KID to recruitment of the polymerase complex versus enhancement of subsequent reaction steps (isomerization, promoter clearance, and reinitiation) showed that the CAD and P-KID act in a concerted mechanism to stimulate transcription. The CAD, but not the KID, mediated recruitment of a complex containing components of a transcription initiation complex, including pol II, IIB, and IID. However, the CAD was relatively ineffective in stimulating subsequent steps in the reaction mechanism. In contrast, phosphorylation of the KID in CREB effectively stimulated isomerization of the recruited polymerase complex and multiple-round transcription. A model for the activation of transcription by phosphorylated CREB is proposed, in which the polymerase is recruited by interaction of the CAD with TFIID and the recruited polymerase is activated further by phosphorylation of the KID in CREB.

Amino Acid Sequence↗
PubMed1998

NPY upregulates genes containing cyclic AMP response element in human neuroblastoma cell lines bearing Y1 and Y2 receptors: involvement of CREB.

Four NPY receptor subtypes have been cloned, and shown to be coupled to both Ca2+ and cAMP. However, very little is known about the downstream elements mediating NPY actions. It has recently been demonstrated in our laboratory that intrahypothalamic (i.h.t.) administration of NPY induces hypothalamic CaM kinase activity, cyclic AMP response element binding protein (CREB) phosphorylation and cyclic AMP response element (CRE) binding activity in rat hypothalamic nuclear proteins. In the present study, we have investigated whether these changes in CRE binding transcriptional factors activated by NPY results in gene regulation using a human neuroblastoma cell line (SK-N-BE2). This cell line which expresses the Y2 subtype of NPY receptors was transfected with a fusion gene containing 1.305 kb of human CRF 5' flanking region with a perfect palindromic CRE site linked to firefly luciferase gene. NPY treatment increased CaM kinase II activity, CREB phosphorylation and CRE binding in these cells. In transfected cells, luciferase activity was also increased by NPY (1.8-4-fold) within 4 h of treatment. Moreover, forskolin (7-30-fold), which stimulates cAMP production, and thapsigargin (6-8-fold), which mobilizes intracellular calcium, also increased luciferase activity within 4 h of treatment. PMA (phorbol-12-myristate-13-acetate), an activator of protein kinase-C, induced luciferase activity by 1.8-fold. NPY augmented forskolin-stimulated luciferase activity from 11- to 15-fold, but had no significant effect on thapsigargin-induced luciferase activity. These findings suggest that activation of protein kinase A (PKA) or CaM kinase leads to the induction of fusion gene. NPY treatment upregulated fusion gene expression through Ca2+ pathway in SK-N-BE2 cell line. Pretreatment with CREB antisense, but not the sense oligodeoxynucleotides, inhibited forskolin-, thapsigargin- and NPY-stimulated luciferase activity. However, CREB sense or antisense oligodeoxynucleotide treatment had no effect on PMA-stimulated luciferase activity. Furthermore, NPY induced CRE binding activity and the expression of CRE containing Y1 receptor gene in SK-N-MC cell line. These findings suggest that NPY can upregulate CRE containing reporter gene including Y1 receptor gene and NPY-induced reporter gene regulation in SK-N-BE2 cells is mediated by intracellular Ca2+ and CREB protein.

Animals↗
PubMed1996

The role of the cyclic AMP-responsive element binding protein (CREB) in hypoxic-ischemic brain damage and repair.

The cyclic AMP-responsive element binding protein (CREB) is a basally expressed, post-translationally activated transcription factor that has been implicated in the trans-activation of a number of genes in response to cAMP and calcium signals. A unilateral hypoxic-ischemic (HI) injury in the 21 day old rat was used to examine a potential role for CREB (phosphorylated and unphosphorylated) in neuronal programmed cell death or cell survival. The selectively vulnerable CAI pyramidal cells, which undergo delayed neuronal death following mild HI, show a loss of CREB and phosphorylated CREB (pCREB) immunoreactivity on the injured side 48 and 72 h following HI. In contrast the resistant dentate granule cells and cortical cells produce a bimodal increase in pCREB immunoreactivity, peaking 6 and 48 h following HI. The fact that cells surviving the HI insult are showing increased activation of CREB suggests that this protein might be involved in the process of neuroprotection.

Animals↗
PubMed1998

Conditional coupling of striatal dopamine D1 receptor to transcription factors: ontogenic and regional differences in CREB activation.

The coupling of striatal dopamine D1 receptors to c-fos transcription exhibit all-or-none regional and ontogenic differences: the D1 agonist SKF 38393 fails to induce c-fos expression in the striatum, except during the early postnatal period in the striosomes, or in the caudal extremity of the striatum in adult animals. In an attempt to better delineate the mechanism responsible for interrupting or enabling this conditional coupling of D1 receptors to c-fos transcription we have examined, through immunocytochemistry and gel shift assay, the activation of the cyclic AMP-response element binding protein (CREB) transcription factor in response to the D1 agonist in the murine striatum. Phosphorylated-CREB (P-CREB) immunoreactivity in response to the dopamine D1 agonist (+/-)SKF 38393 (15 mg/kg, i.p.) was prominent in the caudal extremity of the striatum in adult animals (P90). In neonatal (P5) mice, P-CREB immunoreactive neurons were observed both in the caudal and in the rostral parts of the striatum, without obvious patchy distribution. Gel shift assays performed on nuclear protein extracts from either the rostral or the caudal part of striatal tissue of neonatal (P5) or adult (P90) mice provided quantitative assessment, showing differences both in the amplitude and in the time course of the response, since P-CREB binding in adults culminated 45 min after (+/-)SKF 38393 (15 mg/kg, i.p.) injection, wheareas the peak value appeared as soon as 10 min after injection in P5 mouse pups, suggesting the involvement of partly distinct transduction pathways.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2001

Pairing of forskolin and KCl increases differentiation of immortalized hippocampal neurons in a CREB Serine 133 phosphorylation-dependent and extracellular-regulated protein kinase-independent manner.

Although cAMP response element binding protein (CREB)- and extracellular-regulated protein kinase (ERK)-mediated pathways have been linked to each other in neuronal differentiation, involvement of these in hippocampal neuronal cell line has not been defined. Using an immortalized hippocampal cell line, HiB5, we have tried a pairing of forskolin with KCl depolarization, which acts as an ERK and CREB kinase activator in hippocampal neurons, to investigate if an activation of ERK and phosphorylation of CREB at the critical regulatory site, serine 133 might be coupled in differentiation. Differentiation toward a neuronal phenotype was synergistically and markedly increased by the pairing of forskolin and KCl depolarization. The synergistic effect was accompanied by an increase in phosphorylation of CREB Ser-133, but not phosphorylation of ERK, and was not inhibited by MEK inhibitor, PD98059. These findings indicate that phosphorylation of the transcriptional factor CREB may function to facilitate differentiation of HiB5 cells.

Animals↗
PubMed2002

Increases in the phosphorylation of cyclic AMP response element binding protein (CREB) and decreases in the content of calcineurin accompany thermal hyperalgesia following chronic constriction injury in rats.

Plasticity in the spinal dorsal horn may underlie the development of chronic pain following peripheral nerve injury or inflammation. In this study, we examined whether chronic constriction injury of the sciatic nerve was associated with changes in the immunoreactive content of cyclic AMP response element binding protein (CREB), protein kinase A (PKA), and calcineurin Aalpha and Abeta in the spinal dorsal horn. In animals exhibiting thermal hyperalgesia as a behavioral sign of neuropathic pain 7 days after loose ligation of the sciatic nerve (chronic constriction injury), there was a significant increase in the content of phosphorylated (activated) CREB (pCREB). In contrast, following the typical disappearance of thermal hyperalgesia 28 days after loose ligation surgery, there were no differences in pCREB content between control and sciatic ligation animals. The increased CREB activation associated with thermal hyperalgesia was accompanied by significant decreases in the content of both calcineurin Aalpha and Abeta. In contrast, there were no differences in the content of non-phosphorylated CREB, and phosphorylated or non-phosphorylated PKA between control and sciatic ligation animals either 7 or 28 days after surgery. These data established a close association in the expression of thermal hyperalgesia with CREB activation and decreased calcineurin content in the spinal dorsal horn. The data revealed a significant but reversible shift in the manner in which spinal neurons processed sensory information following peripheral nerve injury, and lent further support to the notion that plasticity in the spinal dorsal horn may have contributed to the development of chronic pain.

Animals↗
PubMed2002

Altered regulation of CREB by chronic antidepressant administration in the brain of transgenic mice with impaired glucocorticoid receptor function.

Various effects of antidepressant drugs on gene transcription have been described and altered gene expression has been proposed as being a common biological basis underlying depressive illness. One target for the common action of antidepressants is a modifying effect on the regulation of postreceptor pathways and genes related to the cAMP cascade. Recent studies have demonstrated that long-term antidepressant treatment resulted in sustained activation of the cyclic adenosine 3',5'-monophosphate system and in increased expression of the transcription factor cAMP response element binding protein (CREB). A transgenic animal model of depression with impaired glucocorticoid receptor function was used to investigate the effect of chronic antidepressant treatments on CREB expression in different brain areas. Wild-type and transgenic mice received one administration of saline, desipramine, or fluoxetine, daily for 21 days. The effects of antidepressants on CREB mRNA were analyzed using a sensitive RNase protection assay. Antidepressant treatment resulted in a neuroanatomically and animal specific expression pattern of CREB. Our findings suggest that life-long central glucocorticoid receptor dysfunction results in an altered sensitivity with respect to the effects of antidepressants on the expression of CREB.

Animals↗
PubMed1996

Genetic dissection of structural and functional components of synaptic plasticity. III. CREB is necessary for presynaptic functional plasticity.

Increased cAMP (in dunce mutants) leads to an increase in the structure and function of the Drosophila neuromuscular junction. Synaptic Fasciclin II (Fas II) controls this structural plasticity, but does not alter synaptic function. Here, we show that CREB, the cAMP response element-binding protein, acts in parallel with Fas II to cause an increase in synaptic strength. Expression of the CREB repressor (dCREB2-b) in the dunce mutant blocks functional but not structural plasticity. Expression of the CREB activator (dCREB2-a) increases synaptic strength only in FasII mutants that increase bouton number. This CREB-mediated increase in synaptic strength is due to increased presynaptic transmitter release. Expression of dCREB2-a in a FasII mutant background genetically reconstitutes this cAMP-dependent plasticity. Thus, cAMP initiates parallel changes in CREB and Fas II to achieve long-term synaptic enhancement.

Animals↗
PubMed1996

Spatiotemporal dynamics of CREB phosphorylation: transient versus sustained phosphorylation in the developing striatum.

The cAMP response element-binding protein (CREB) is a plasticity-associated transcription factor that can potentially integrate cAMP and calcium signals at the gene activation level. We tested for convergent Ser-133 phosphorylation of CREB via dopamine D1/D5 receptors and L-type calcium channels in organotypic cultures of neonatal striatum. We found such convergence only transiently. Sustained CREB phosphorylation by D1/D5 receptor and L-type channel agonists was targeted to opposite (striosome and matrix) cellular phenotypes. Subsequent expression of the CRE-containing gene, c-fos, matched the divergent patterns of sustained CREB phosphorylation, and both divergent patterns could be switched by inhibition of phosphatases, including calcineurin. Control of the duration of CREB phosphorylation may be a critical regulator of CRE-mediated gene expression by dopamine and calcium.

Animals↗