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PubMed1995

The cyclic adenosine 3',5'-monophosphate-responsive factor CREB is constitutively activated in human somatotroph adenomas.

Oncogenic gsp proteins appear to stimulate the transformation of pituitary somatotrophs by inducing the constitutive activation of adenyl cyclase. Previous work implicating the cAMP-responsive transcription factor CREB as a biochemical intermediate in the proliferative response to cAMP led us to examine whether CREB activity was correspondingly elevated in human somatotroph adenomas. In a series of 15 human GH-secreting tumors, we found that each of these contained elevated levels of Ser133-phosphorylated and, hence, activated CREB compared with nonfunctioning pituitary tumors. Four of the GH-secreting adenomas contained an oncogenic gsp gene by polymerase chain reaction analysis, and two additional adenomas expressed wild-type G alpha s protein at 5- to 10-fold higher levels than nonfunctioning pituitary tumors. As both oncogenic gsp and overexpressed G alpha s proteins can induce Ser133 phosphorylation and cAMP-responsive gene expression in transfected GC somatotroph cells, our studies indicate that these proteins may promote somatotroph transformation in part by inducing the transcription of specific CREB-dependent target genes.

Adenoma↗

PubMed2001

Vitronectin regulates Sonic hedgehog activity during cerebellum development through CREB phosphorylation.

During development of the cerebellum, Sonic hedgehog (SHH) is expressed in migrating and settled Purkinje neurons and is directly responsible for proliferation of granule cell precursors in the external germinal layer. We have previously demonstrated that SHH interacts with vitronectin in the differentiation of spinal motor neurons. Here, we analysed whether similar interactions between SHH and extracellular matrix glycoproteins regulate subsequent steps of granule cell development. Laminins and their integrin receptor subunit alpha6 accumulate in the outer most external germinal layer where proliferation of granule cell precursors is maximal. Consistent with this expression pattern, laminin significantly increases SHH-induced proliferation in primary cultures of cerebellar granule cells. Vitronectin and its integrin receptor subunits alpha(v) are expressed in the inner part of the external germinal layer where granule cell precursors exit the cell cycle and commence differentiation. In cultures, vitronectin is able to overcome SHH-induced proliferation, thus allowing granule cell differentiation. Our studies indicate that the pathway in granule cell precursors responsible for the conversion of a proliferative SHH-mediated response to a differentiation signal depends on CREB. Vitronectin stimulates phosphorylation of cyclic-AMP responsive element-binding protein (CREB), and over-expression of CREB is sufficient to induce granule cell differentiation in the presence of SHH. Taken together, these data suggest that granule neuron differentiation is regulated by the vitronectin-induced phosphorylation of CREB, a critical event that terminates SHH-mediated proliferation and permits the differentiation program to proceed in these cells.

Animals↗

PubMed2004

CREB and neurodegeneration.

Programmed cell death (PCD) is major concept in neurobiology and transcription factors are pivotal in switching on the nerve cell death program. More recently, the transcriptional control of programmed cell life (PCL) is beginning to be understood. This work began in studies of the activation of the CREB transcription factor in stroke models where it was shown that CREB is phosphorylated (and presumably activated) in neurons that survive this insult. In this review I will describe this data and also discuss the up-stream and down-stream pathways in this CREB neuroprotective transcriptional cassette. Finally, I will discuss studies showing that this CREB survival pathway may be inactivated by neurotoxins and genes involved in neurodegenerative disorders.

Animals↗

PubMed2000

The inducible cAMP early repressor ICERIIgamma inhibits CREB and AP-1 transcription but not AT1 receptor gene expression in vascular smooth muscle cells.

Growth factors and agonists of both G alpha s and G alpha q-coupled receptor agonists each down regulate angiotensin AT1 receptor gene expression in vascular smooth muscle cells. To test whether the transcription factor CREB is in the pathway involved in modulation of AT1-receptor gene expression, AT1 receptor mRNA levels were measured after stimulation with forskolin, angiotensin II and PDGF-BB in VSMC expressing the inducible cAMP early repressor protein, ICERIIgamma, fused to the green fluorescent protein (eGFP). This fusion protein inhibits luciferase induction from promoters driven by either CREB response elements (CRE) or, unexpectedly, by tetradecanoylphorbol acetate response elements (TRE), which bind activator protein (AP-1). EGFP-ICERIIgamma expression inhibits occupancy of CRE and TRE elements by endogenous VSMC nuclear proteins. Nevertheless, agonist-induced AT1-receptor mRNA down regulation is unaffected by eGFP-ICERIIgamma expression. Although CREB transcription is activated by multiple classes of agonists in VSMC, and ICER can inhibit agonist-induced transcription mediated by both CREB and AP-1 enhancers, these transcription factors are not obligate components of the pathways regulating AT1-R gene expression in rat VSMC.

Angiotensin II↗

PubMed2000

ZNC(C)PR Induces Phosphorylation of CREB in Rat Hippocampus.

ZNC(C)PR can facilitate the learning and memory in rat. Transgenic experiments have revealed that long-term memory depended on cyclic AMP-response element binding protein, CREB. CREB phosphorylation at serine-133 is essential for it's transcriptional activity. Here, it was demonstrated that ZNC(C)PR could induce CREB phosphorylation at serine-133 in both rat hippocampus and rat hippocampus slices. ZDC(C)PR antagnist of ZNC(C)PR , PTX(inhibitor of G(o)/G(I) protein coupled receptor), GF109203x(inhihitor of PKC), PD98059( inhibitor of MAPK ) but not KN-62(inhibitor of CaMKII) could inhibit the phosphorylation of CREB induced by ZNC(C)PR.

Journal Article↗

PubMed2006

Changes of learning, memory and levels of CaMKII, CaM mRNA, CREB mRNA in the hippocampus of chronic multiple-stressed rats.

BACKGROUND: The effect of chronic stress on cognitive functions has been one of the hot topic in neuroscience. But there has been much controversy over its mechanism. Such single stressor applied in the past could not simulate complicated living circumstances that people confronted with. The aim of this study was to investigate the effects of chronic multiple-stress on learning and memory as well as on the levels of calcium/calmodulin-dependent protein kinase II (CaMKII), calmodulin (CaM) mRNA, and cAMP-response element binding protein (CREB) mRNA in the hippocampus of rats. METHODS: The rats were divided randomly into stressed and control groups. The stressed group was given chronic multiple-stress for 6 weeks to set up a chronic multiple-stressed model. The rats' performance of spatial learning and memory was tested using Morris Water Maze (MWM) and Y-maze. Meanwhile, the expressions of CaMKII, CaM mRNA and CREB mRNA of rats' hippocampus were detected by immunohistochemistry, Western blot and reverse transcription-polymerase chain reaction (RT-PCR), respectively. In addition, the width of synaptic cleft and the thickness of post-synaptic densities (PSD) were observed in the hippocampal CA3 region of rats by electron microscopy. RESULTS: After exposure to chronic multiple-stress for 6 weeks, the ability of learning and memory of the stressed group was higher than that of the control group (P < 0.05, P < 0.01). The width of synaptic cleft was smaller and the thickness of PSD was larger in the hippocampal CA3 region of the stressed group than in that of the control group (P < 0.01). The CaMK II immunostaining of the stressed group was stronger than that of the control group in the stratum radiatum and oriens of the hippocampal CA1 and CA3, especially in the stratum oriens. Quantitative analysis indicated that the expression of CaMK II, CaM mRNA, and CREB mRNA in the hippocampus of the stressed group was higher than that of the control group (P < 0.05, P < 0.01). CONCLUSIONS: The capacity of learning and memory can be enhanced after chronic multiple-stress. The increased levels of CaMK II, CaM mRNA, and CREB mRNA may contribute to the enhancing effect of chronic multiple-stress on learning and memory.

Animals↗

PubMed1995

Spatial memory deficits, increased phosphorylation of the transcription factor CREB, and induction of the AP-1 complex following experimental brain injury.

Traumatic brain injury causes both short- and long-term neurological impairments. A cascade of biochemical changes triggered by the injury may increase the expression of several genes, which has been hypothesized to contribute to the observed cognitive deficits. The mechanism(s) of induction for these genes is not yet known. We present evidence that lateral cortical impact injury in rats that produces spatial memory deficits also increases phosphorylation of the transcription factor CREB (cAMP response element binding). Subsequent to the phosphorylation of CREB, c-Fos expression and the AP-1 complex are enhanced. The temporal and spatial activation of c-Fos is consistent with it being induced by phosphorylated CREB proteins. Thus, CREB-mediated gene activation may contribute to the observed behavioral deficits. Further elucidation of the biochemical and pathophysiological changes will be of importance for clinical therapy.

Animals↗

PubMed1994

Inhibition by insulin of protein kinase A-induced transcription of the phosphoenolpyruvate carboxykinase gene. Mediation by the activation domain of cAMP response element-binding protein (CREB) and factors bound to the TATA box.

The minimal promoter/transcription factor requirements for induction of phosphoenolpyruvate carboxykinase (PEPCK) transcription by cAMP-activated protein kinase A (PKA) and inhibition of this induction by insulin were investigated. H4 hepatoma cells were treated with or without insulin following cotransfection with chloramphenicol acetyltransferase reporter genes and expression vectors coding for the cAMP response element-binding protein (CREB) activation domain fused to the GAL4 DNA binding domain (CRG) and the catalytic subunit of PKA. Mutation of the PEPCK CRE to a GAL4 binding site (G4-PEPCK) within the fully responsive PEPCK promoter (-600/+69) made induction by PKA dependent upon cotransfection of CRG and this induction by CRG+PKA was inhibited by insulin. Mutation of the insulin regulatory sequence (delta IRS-G4-PEPCK) did not prevent induction by cAMP or inhibition by insulin. Fusion of GAL4 binding sites to the PEPCK TATA region (-40/+1, G4-PT) allowed induction by CRG+PKA and inhibition by insulin. However, inhibition by insulin was not observed when the CREB activation domain in CRG was replaced with the activation domain of VP16 (G4-VP16) or when the PEPCK TATA region was replaced with TATA regions from other genes. Our results indicate that the minimal requirements for induction of PEPCK by PKA and inhibition by insulin include: 1) the CREB activation domain, 2) the PEPCK TATA sequence, and 3) insulin-responsive hepatoma cells. These data suggest that specific factors interacting with both the PEPCK TATA region and the CREB activation domain are required for insulin inhibition of PKA-induced transcription.

Animals↗

PubMed1994

Differential regulation of respiratory chain subunits by a CREB-dependent signal transduction pathway. Role of cyclic AMP in cytochrome c and COXIV gene expression.

In vertebrate organisms, the molecular mechanisms by which extracellular signals regulate mitochondrial function and biogenesis are largely unknown. We have previously identified multiple cis-acting elements in both cytochrome c and cytochrome oxidase subunit IV (COXIV) genes that are likely targets for the regulated expression of respiratory chain components. We now demonstrate that cytochrome c but not COXIV mRNA is induced by cAMP through a mechanism involving transcriptional activation. Maximal induction occurs within 3 h and does not require de novo protein synthesis. The differential response of these genes is mediated by two distinct cAMP response elements (CREs) in the cytochrome c promoter region. Both elements function independently to drive cAMP-dependent expression from a heterologous promoter and within the proper cytochrome c promoter context. In addition, the binding properties of both elements to nuclear factors were characterized by competition DNase I footprinting, methylation interference footprinting, site-directed mutagenesis, and UV-induced DNA-protein cross-linking. The results are all consistent with the specific recognition of both CREs by CRE binding protein (CREB). A highly purified preparation of recombinant CREB formed a specific complex with each of the cytochrome c CREs identical to that formed with a crude nuclear fraction. In addition, the trans-activation of cytochrome c gene expression by recombinant CREB and protein kinase A in transfected cells was completely dependent on functional CREs within the promoter. These results establish that respiratory chain gene expression can be regulated directly by cAMP through a CREB-dependent signal transduction pathway.

Animals↗

PubMed1993

Transactivation by the human T-cell leukemia virus Tax protein is mediated through enhanced binding of activating transcription factor-2 (ATF-2) ATF-2 response and cAMP element-binding protein (CREB).

The human T-cell leukemia virus type I (HTLV-I)-encoded transcriptional activator protein Tax is strongly implicated in HTLV-I pathogenesis. Tax regulates HTLV-I gene expression through three 21-base pair (bp) repeat enhancer elements located in the transcriptional control region of the virus. Tax does not bind these elements directly, but mediates transactivation through the cellular transcription factors that recognize a cAMP response element (CRE)-like sequence centered within each of the 21-bp repeats. In this report, we identify activating transcription factor-2 (ATF-2) and CRE-binding protein (CREB) as the principal T-cell proteins that bind the three 21-bp repeats in vitro. Purified Tax protein augments the level of RNA synthesis induced by ATF-2 and CREB in a cell-free transcription assay, providing evidence that Tax cooperates with these cellular proteins to activate HTLV-I transcription. Furthermore, Tax dramatically increases the binding of both the T-cell-derived and recombinant forms of ATF-2 and CREB to each of the 21-bp repeats. The target sequences for this enhancement reside within the DNA binding/dimerization domains of these proteins. These data suggest that Tax transactivates HTLV-I gene expression by increasing the number of bound ATF-2 and CREB molecules at the viral promoter.

Activating Transcription Factor 2↗

PubMed1993

A peptide containing the leucine zipper domain specifically inhibits CREB binding and transcription.

Formation of dimers via leucine zippers is an absolute requirement for several transcription factors to express their activity. Using circular dichroism spectroscopy, it was found that synthetic peptides which mimic the leucine zippers from CREB, Jun and Myc are alpha-helices in solution. The CREB leucine zipper peptide specifically inhibited the binding of wild type CREB protein and transcription from the CRE containing c-fos promoter in vitro. This inhibition is most likely caused by competition of the peptide to form complex with CREB monomers through leucine zippers.

Amino Acid Sequence↗

PubMed2007

Transforming growth factor-beta2 modulates synaptic efficacy and plasticity and induces phosphorylation of CREB in hippocampal neurons.

Transforming growth factor-betas (TGF-betas) are widely expressed and play roles as multifunctional growth factors and regulators of key events in development, disease, and repair. However, it is not known whether TGF-betas affect the plasticity of hippocampal neurons. As a first step to address this issue, we examined whether TGF-beta2 modulated the electrophysiological and biochemical properties of cultured hippocampal neurons. We found that prolonged 24 h treatment with TGF-beta2 induced facilitation of evoked postsynaptic currents (ePSCs). This facilitation was associated with a decrease in short-term synaptic depression of ePSCs and increases in both the amplitude and frequency of spontaneous miniature postsynaptic currents (mPSCs). The long-term changes of ePSCs and mPSCs may be associated with cAMP response element-binding protein (CREB), which has been previously implicated in long-term potentiation. Immunofluorescence techniques and Western blot analysis both revealed that TGF-beta2 enhanced the phosphorylation of CREB. Together, these results suggest that TGF-beta2 may play a role in the cascade of events underlying long-term synaptic facilitation in hippocampus, and that CREB may be an important mediator of these effects.

Analysis of Variance↗

PubMed2006

CREB-dependent cyclooxygenase-2 and microsomal prostaglandin E synthase-1 expression is mediated by protein kinase C and calcium.

Cellular production of prostaglandins (PGs) is controlled by the concerted actions of cyclooxygenases (COX) and terminal PG synthases on arachidonic acid in response to agonist stimulation. Recently, we showed in an ileal epithelial cell line (IEC-18), angiotensin II-induced COX-2-dependent PGI2 production through p38MAPK, and calcium mobilization (J. Biol. Chem. 280: 1582-1593, 2005). Agonist binding to the AT1 receptor results in activation of PKC activity and Ca2+ signaling but it is unclear how each pathway contributes to PG production. IEC-18 cells were stimulated with either phorbol-12,13-dibutyrate (PDB), thapsigargin (TG), or in combination. The PG production and COX-2 and PG synthase expression were measured. Surprisingly, PDB and TG produced PGE2 but not PGI2. This corresponded to induction of COX-2 and mPGES-1 mRNA and protein. PGIS mRNA and protein levels did not change. Activation of PKC by PDB resulted in the activation of ERK1/2, JNK, and CREB whereas activation of Ca2+ signaling by TG resulted in the delayed activation of ERK1/2. The combined effect of PKC and Ca2+ signaling were prolonged COX-2 and mPGES-1 mRNA and protein expression. Inhibition of PKC activity, MEK activity, or Ca2+ signaling blocked agonist induction of COX-2 and mPGES-1. Expression of a dominant negative CREB (S133A) blocked PDB/TG-dependent induction of both COX-2 and mPGES-1 promoters. Decreased CREB expression by siRNA blocked PDB/TG-dependent expression of COX-2 and mPGES-1 mRNA. These findings demonstrate a coordinated induction of COX-2 and mPGES-1 by PDB/TG that proceeds through PKC/ERK and Ca2+ signaling cascades, resulting in increased PGE2 production.

Animals↗

PubMed2005

Interleukin-1beta induces CREB-binding protein (CBP) mRNA in brain and the sequencing of rat CBP.

Interleukin-1 beta (IL-1) and CREB have many CNS actions including sleep regulation and hippocampal-dependent learning. CREB acts in part via CREB-binding protein (CBP). We thus determined whether IL-1 could induce CBP gene expression. Initially, cultured hippocampal cells were treated with IL-1 and differential display reverse transcription was used to identify up- and down-regulated genes. We then sequenced rat CBP. Of the IL-1-upregulated genes, CBP and adenine nucleotide translocator-1 (ANT-1) were investigated in vivo. In these experiments, IL-1 was given to rats intraventricularly and sacrificed 2 h later; both CBP and ANT-1 transcripts were upregulated in the cerebral cortex and hypothalamus. We conclude that rat CBP shares many of the functional domains as human and murine CBP and that IL-1 upregulates genes previously associated with learning and sleep.

Adenine Nucleotide Translocator 1↗

PubMed2006

Nobiletin restoring beta-amyloid-impaired CREB phosphorylation rescues memory deterioration in Alzheimer's disease model rats.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive and memory deterioration. Production and accumulation of beta-amyloid peptide (Abeta) is central to the pathogenesis of AD. Recent studies have demonstrated that PKA/CREB-dependent signaling pathway and long-term potentiation are inhibited by sublethal concentrations of Abeta(1-42) in cultured hippocampus neurons. Here, we examined the effects of nobiletin on the Abeta-induced inhibition of CREB phosphorylation in cultured rat hippocampus neurons. A sublethal concentration of Abeta(1-42) or Abeta(1-40) decreased glutamate-induced CREB phosphorylation, whereas pretreatment with nobiletin reversed the Abeta-induced decrease in CREB phosphorylation. The effects of nobiletin on impairment of learning ability were also examined in chronically Abeta(1-40) infused AD model rats using the eight-arm radial maze. In the AD model rats, nobiletin showed protective effects on Abeta(1-40)-induced impairment of learning ability. These results suggest that nobiletin has the potential for becoming a novel lead compound for drug development for AD.

Alzheimer Disease↗

PubMed2005

Unique patterns of FOS, phospho-CREB and BrdU immunoreactivity in the female rat brain following chronic stress and citalopram treatment.

Affective disorders are common psychiatric illnesses characterized by marked gender-related prevalence. Recent evidence links chronic stress and dysregulation of neurotrophin signaling with the development of depression, while novel theories suggest that antidepressants may act by promoting intracellular adaptations linked to neuroplasticity. Although selective serotonin reuptake inhibitors (SSRIs) efficaciously improve a variety of dysfunctions in males, their neuroendocrine effects and intracellular signaling patterns in females are not well determined. Here we show that chronic footshock stress (21 days) promotes HPA axis hyperactivity (as seen by the increased FOS-ir in the paraventricular hypothalamic nucleus (PVN), plasma corticosterone and adrenal hypertrophy), reduces hippocampal BrdU immunoreactivity and suppresses cortical-limbic CREB phosphorylation in female rats. Long-term citalopram treatment, in contrast, attenuates stress-induced elevation of corticosterone levels and adrenal hypertrophy, although it does not reverse footshock-mediated induction of FOS-ir in the PVN, inhibition of CREB phosphorylation and reduction of hippocampal BrdU-labeling. Moreover, citalopram administration was also associated with significant hypophagic effects and inhibition of CREB phosphorylation. These data suggest that, in female rats, normalization of chronic stress-induced HPA axis abnormalities may represent an initial phase of citalopram-mediated therapeutic actions and despite this SSRI's apparent lack of effects on neuroplasticity, we cannot exclude the possibility that some neurochemical adaptations occur in a later stage which may require more than 3 weeks of treatment to manifest.

Animals↗

PubMed1999

Signaling routes to CREM and CREB: plasticity in transcriptional activation.

The CREB and CREM transcription factors are activated by phosphorylation of a key serine residue by kinases stimulated by cyclic AMP, Ca2+, growth factors and stress signals. Phosphorylation allows recruitment of CREB-binding protein (CBP), a large co-activator that contacts the general transcriptional machinery. Studies of the physiological roles played by CREB and CREM have uncovered novel routes of transcriptional activation. For example, in male germ cells CREM is not phosphorylated but associates with ACT, a member of the LIM-only class of proteins that has intrinsic transcriptional activity. Thus, in some circumstances, CREM can bypass the classical requirement for phosphorylation and association with CBP.

Animals↗

PubMed1999

CBP-independent activation of CREM and CREB by the LIM-only protein ACT.

Transcriptional activation by CREB and CREM requires phosphorylation of a serine residue within the activation domain (Ser 133 in CREB; Ser 117 in CREM) which as a result interacts with the coactivator CBP. The activator CREM is highly expressed in male germ cells and is required for post-meiotic gene expression. Using a two-hybrid screen, we have isolated a testis-derived complementary DNA encoding a protein that we term ACT (for activator of CREM in testis), a LIM-only protein which specifically associates with CREM. ACT is expressed coordinately with CREM in a tissue- and developmentally regulated manner. It strongly stimulates CREM transcriptional activity in yeast and mammalian cells and contains an intrinsic activation function. As ACT bypasses the classical requirements for activation, namely phosphorylation of Ser 117 and interaction with CBP, it represents a new route for transcriptional activation by CREM and CREB. ACT may define a previously undiscovered class of tissue-specific coactivators whose function could be specific for distinct cellular differentiation programmes.

Amino Acid Sequence↗