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PubMed1998

Human T-cell leukemia virus type 1 Tax requires direct access to DNA for recruitment of CREB binding protein to the viral promoter.

Efficient human T-cell leukemia virus type 1 (HTLV-1) replication and viral gene expression are dependent upon the virally encoded oncoprotein Tax. To activate HTLV-1 transcription, Tax interacts with the cellular DNA binding protein cyclic AMP-responsive element binding protein (CREB) and recruits the coactivator CREB binding protein (CBP), forming a nucleoprotein complex on the three viral cyclic AMP-responsive elements (CREs) in the HTLV-1 promoter. Short stretches of dG-dC-rich (GC-rich) DNA, immediately flanking each of the viral CREs, are essential for Tax recruitment of CBP in vitro and Tax transactivation in vivo. Although the importance of the viral CRE-flanking sequences is well established, several studies have failed to identify an interaction between Tax and the DNA. The mechanistic role of the viral CRE-flanking sequences has therefore remained enigmatic. In this study, we used high resolution methidiumpropyl-EDTA iron(II) footprinting to show that Tax extended the CREB footprint into the GC-rich DNA flanking sequences of the viral CRE. The Tax-CREB footprint was enhanced but not extended by the KIX domain of CBP, suggesting that the coactivator increased the stability of the nucleoprotein complex. Conversely, the footprint pattern of CREB on a cellular CRE lacking GC-rich flanking sequences did not change in the presence of Tax or Tax plus KIX. The minor-groove DNA binding drug chromomycin A3 bound to the GC-rich flanking sequences and inhibited the association of Tax and the Tax-CBP complex without affecting CREB binding. Tax specifically cross-linked to the viral CRE in the 5'-flanking sequence, and this cross-link was blocked by chromomycin A3. Together, these data support a model where Tax interacts directly with both CREB and the minor-groove viral CRE-flanking sequences to form a high-affinity binding site for the recruitment of CBP to the HTLV-1 promoter.

Binding Sites↗
PubMed2001

Interactions between CBP, NF-kappaB, and CREB in the lungs after hemorrhage and endotoxemia.

The transcriptional regulatory factor nuclear factor (NF)-kappaB has a central role in modulating expression of proinflammatory mediators that are important in acute lung injury. In vitro studies have shown that competition between NF-kappaB and cAMP response element binding protein (CREB) for binding to the coactivator CREB-binding protein (CBP) is important in regulating transcriptional activity of these factors. In the present study, we examined in vivo interactions between CBP, CREB, and NF-kappaB in hemorrhage- or endotoxemia-induced acute lung injury. Association of CBP with CREB or the p65 subunit of NF-kappaB increased in the lungs after hemorrhage or endotoxemia. Inhibition of xanthine oxidase before hemorrhage, but not before endotoxemia, decreased p65-CBP interactions while increasing those between CREB and CBP. These alterations in CREB-CBP and p65-CBP interactions were functionally significant because xanthine oxidase inhibition before hemorrhage resulted in increased expression of the CREB-dependent gene c-Fos and decreased expression of macrophage inflammatory protein-2, a NF-kappaB-dependent gene. The present results show that the coactivator CBP has an important role in modulating transcription in vivo under clinically relevant pathophysiological conditions.

Animals↗
PubMed1997

Role of a transcription factor (CREB) in memory processes.

Memory storage includes a short-term phase (STM) which requires the phosphorylation of pre-existing proteins, and a long-term phase (LTM) which needs the novel synthesis of RNA and proteins. Cyclic AMP and a specific transcription factor (cAMP response element binding protein or CREB) play a central role in the formation of LTM in aplysia, drosophila and mice. Following its phosphorylation by protein kinase A, CREB binds to the enhancer element CRE which is located in the upstream region of cAMP-responsive genes, thus triggering transcription. Some of the newly-synthesized proteins are additional transcription factors that ultimately give rise to the activation of late response genes, whose products are responsible for the modification of synaptic efficacy leading to LTM. In aplysia, CREB activation has been interfered with by microinjection of CRE containing oligonucleotides into cultured neurons. Under these conditions LTM is blocked while STM remains unchanged. In drosophila, CREB function has been disrupted using a reverse genetic approach. Thus, LTM has been specifically blocked by the induced expression of a CREB repressor isoform, and enhanced by the induced expression of an activator isoform. In mouse, the role of CREB has been confirmed by behavioural analyses of a knock-out line with a targeted mutation in the CREB gene. In these mutants, learning and STM are normal, whereas LTM is disrupted. On the whole, the data suggest that encoding of long term memories involve highly conserved molecular mechanisms.

Animals↗
PubMed1999

Phosphorylation of CREB in axon-induced Schwann cell proliferation.

Axonal contact regulates Schwann cell (SC) proliferation during development. However, the intracellular signal transduction pathways involved in the axon-induced proliferation of SC have not been described. We have previously shown that SC proliferation induced by axolemma-enriched fractions (AEF) is accompanied by increased expression of cyclic AMP-responsive element binding protein, CREB. We now report the AEF and dorsal root ganglion neuritic-induced signal transduction pathway(s) which regulate the phosphorylation of CREB that correlate with the SC proliferative response. The phosphorylated form of CREB was significantly increased after 16 hr of axonal stimulation, continued to increase for 48 hr, and subsequently decreased as monitored by immunocytochemistry and Western blot analysis. Treatment with protein kinase A (PKA) inhibitor, H89, completely abolished both the CREB activation and SC proliferation. In contrast, treatment with protein kinase C (PKC) inhibitor (bisindolylmaleimide) inhibited AEF-induced SC proliferation, but did not immediately affect CREB phosphorylation. These data are consistent with the view that PKA and PKC pathways are essential for AEF-induced SC proliferation. Since PKC can influence SC proliferation without initially affecting CREB phosphorylation, PKC may regulate SC proliferation at pathways distal to the immediate CREB activation.

Animals↗
PubMed2004

Regulation of the CREB signaling cascade in the visual cortex by visual experience and neuronal activity.

The cAMP-responsive element (CRE) regulatory pathway has been studied as a model of signal-regulated transcription and is critical for some forms of learning and adaptation. In cell culture systems, the extracellular-regulated kinase (ERK) and ribosomal S6 kinase (RSK) couple synaptic signals to CRE-mediated gene expression by modulating CRE-binding protein (CREB) phosphorylation. However, it is not known whether sensory experience regulates gene expression in the brain by this mechanism. In this study, we ask: Are activated forms of ERK, RSK, and CREB colocalized in the cortex and are they coordinately regulated by synaptic signals? We find that these three signaling components are regulated in distinct ways. First, cells that show CRE-lacZ reporter expression, primarily excitatory neurons, do not colocalize with cells containing phospho-ERK. Second, while phosphorylation of ERK and RSK are modulated by visual experience, phosphorylation of CREB at serines 133, 142, or 143 is detected constitutively and is unaffected by experience. This finding suggests that neural activity might not regulate CREB phosphorylation in vivo. To test this hypothesis, we blocked action potentials by injection of tetrodotoxin and found no effect on CREB phosphorylation. These in vivo data show that, in contrast to cell culture systems, cortical synaptic activity controls CRE-mediated gene expression without affecting CREB phosphorylation, possibly by modification of RSK and CREB-associated coregulators.

Action Potentials↗
PubMed2006

Survival of DA neurons is independent of CREM upregulation in absence of CREB.

cAMP response element binding protein (CREB) and the related factors CREM (cAMP response element modulator) and ATF1 (activation transcription factor 1) are bZIP-domain-containing transcription factors activated through cAMP and other signaling pathways. The disruption of CREB function in developing and mature neurons affects their development and survival when associated with loss of CREM. Since dopaminergic (DA) neurons are affected in several neurological diseases, we generated CREB conditional mutants in DA neurons by using a newly generated transgenic Cre line targeting the dopaminergic system (DATCre). Here we report the generation and analysis of mutant mice lacking CREB in DA neurons (CREB(DATCre) mutants). During adulthood, lack of CREB leads to a partial loss of DA neurons. Since CREM is upregulated in absence of CREB, we have introduced this mutation in a CREM-/- genetic background to assess a compensatory role of CREM. Additional inactivation of CREM does not lead to a more severe phenotype.

Animals↗
PubMed2005

Activation of CREB by tauroursodeoxycholic acid protects cholangiocytes from apoptosis induced by mTOR inhibition.

Tauroursodeoxycholic acid (TUDCA) is a cytoprotective bile acid frequently prescribed to patients with cholestatic diseases. Several mechanisms of action have been investigated, but the possibility that cyclic adenosine monophosphate responsive element binding protein (CREB), a transcription factor promoting cell survival, mediates TUDCA's protective effects has not been considered. We examined whether TUDCA activates CREB and whether this activation can protect biliary epithelial cells. Cholangiocytes were stressed by exposure to CCI-779, which inhibits signaling though the kinase mTOR (mammalian target of rapamycin), resulting in cell cycle arrest and apoptosis. Incubation of normal rat cholangiocytes (NRC) cells, with TUDCA resulted in phosphorylation of CREB (Western blotting analysis) and activation of CREB transcription activity (luciferase reporter assay). Inhibition of calcium signals and inhibition of protein kinase C prevented the TUDCA-induced activation of CREB. CCI-779 decreased the viability of rat cholangiocytes in a dose-dependent manner (MTT [3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay). TUDCA protected against CCI-779 cytotoxicity. A dominant negative form of CREB was stably transduced in NRC cells (NRC-M1). TUDCA protection was decreased in NRC-M1. While CCI-779 induced apoptosis in NRC cells as determined by caspase 3 activity, TUDCA attenuated CCI-779-induced apoptosis, an effect absent in NRC-M1. Finally, CCI-779 blocked proliferation of both NRC and NRC-M1 (thymidine incorporation) and this was unaffected by TUDCA. In conclusion, TUDCA activates CREB in cholangiocytes, reducing the apoptotic effect of CCI-779. These findings suggest a novel cytoprotective mechanism for this bile acid.

Animals↗
PubMed1990

Both the basic region and the 'leucine zipper' domain of the cyclic AMP response element binding (CREB) protein are essential for transcriptional activation.

Second messengers like cAMP can activate the transcription of genes containing consesus cAMP response element (CRE). A 43 kd nuclear phosphoprotein previously identified as the cAMP response element binding (CREB) protein has been shown to bind as a dimer to CRE and activate gene transcription. The rat and human CREB protein contain the 'leucine zipper' motif. We have analyzed the role of both leucine zipper domain and the amino-terminal basic region by making site-specific mutations. Our results show that the first three leucines int he leucine zipper domain are essential for efficient dimer formation. Mutations of two consecutive leucines in the leucine zipper domain completely abolish the ability to form dimers. Mutant CREB protein unable to form homodimers is also unable to bind to DNA. In contrast, however, mutations, in the DNA binding region had no effect on dimer formation but were unable to bind to CRE sites or activate transcription. We propose that CREB protein functions by forming homodimers which bind to CRE and activate transcription. Furthermore, the CREB protein needs to be phosphorylated before activating transcription. Finally, we show that the CREB basic region mutant acts as a trans-dominant transcriptional suppressor of wild-type CREB function.

Animals↗
PubMed2004

Activation of Akt/PDK signaling in macrophages upon binding of receptor-recognized forms of alpha2-macroglobulin to its cellular receptor: effect of silencing the CREB gene.

Macrophage binding of receptor-recognized forms of alpha2-macrogobulin (alpha2M*) significantly increases cAMP, CREB, and activated CREB. We have now examined the participation of the PI 3-kinase/PDK/Akt/p70s6k signaling cascade in alpha2M*-induced cellular proliferation and also studied the role of CREB in these events. Exposure of cells to alpha2M* caused an approximately 2-fold increase in CREB and its phosphorylation at Ser133, phosphorylation of the regulatory subunit of PI 3-kinase, Akt phosphorylation at Ser473 or Thr308, and phosphorylated 70s6k. Silencing of the CREB gene with dsRNA homologous in sequence to the target gene, markedly reduced the levels of CREB mRNA activation of CREB, PI 3-kinase, Akt, and p70s6k in alpha2M*-stimulated macrophages. We conclude that in murine peritoneal macrophages, alpha2M*-induced increase of cAMP is involved in cellular proliferation and this process is mediated by the PI 3-kinase signaling cascade.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed1994

Oligodendroglial cyclic AMP response element-binding protein: a member of the CREB family of transcription factors.

Several laboratories have shown that cyclic AMP (cAMP) plays an important role in inducing oligodendrocyte differentiation and myelin synthesis. Our previous results have shown that oligodendrocytes contain a nuclear protein that binds to the DNA sequence TGACGTCA or cAMP response element (CRE) known to be involved in the transcriptional regulation of cAMP-responsive genes. In this report the oligodendroglial CRE-binding protein was further identified by using two different antibodies which specifically recognize the CRE-binding protein known as CREB. In DNA-shift assays CREB-1(X-12) antibody interacted with the CRE-protein complexes resulting in further retardation ("super shift") of the mobility of the bands in the gels. Immunoprecipitation of oligodendroglial nuclear extracts with CREB(240) antibody prior to the DNA binding assays resulted in a lack of formation of CRE-protein complexes. In addition immunoreaction with CREB(240) antibody identified the CRE-binding species as a 45 kDa phosphoprotein. Immunocytochemical staining with CREB(240) antibody in oligodendrocytes from 10-, 14-, and 18-day-old and adult rats indicated that this protein is expressed before the appearance of myelin basic protein (MBP) which was used as a marker of myelin synthesis. Collectively, these observations support our previous results and indicate that the oligodendroglial CRE-binding protein species is highly homologous to the CREB protein. The developmental expression of this CREB protein supports the idea of a possible role during the early stages of oligodendrocyte differentiation preceding the peak of myelin synthesis in rat CNS.

Animals↗
PubMed1993

Expression of JUN, KROX, and CREB transcription factors in goldfish and rat retinal ganglion cells following optic nerve lesion is related to axonal sprouting.

Goldfish and rat optic nerves were cut and crushed, respectively, and the expression of the transcription factor proteins c-JUN, JUN B, JUN D, c-FOS, FOS B, KROX-24, and CREB was investigated in retinal ganglion cells (RGCs) by immunocytochemistry. Immunoreactivities (IRs) were followed up to 350 days in the goldfish and up to 22 days in the rat. In RGCs of untreated goldfish and rats, all JUN, FOS, and KROX proteins were absent whereas CREB was constitutively expressed. After optic nerve cut in goldfish, a JUN-like immunoreactivity (JUN-IR) appeared in a small number of RGCs of central retina after 24 h, reached a maximum within 5 days, declined after 30 days, and was on a half-maximal level after 50 days. Between 100 and 200 days, JUN-IR was only visible in a few RGCs and was completely absent after 350 days. Specific antibodies against c-JUN, JUN B, and JUN D gave no distinct immunoreactive signal. Thus, we could not determine which member of the JUN family contributed to the JUN-IR. The expression of CREB declined after 5 days. The number of CREB-labeled RGCs was reduced (not significant) and the intensity of labeling faded out. After 50 days, CREB-IR had returned to basal level. c-FOS, FOS B, and KROX-24 could not be detected in goldfish RGCs following optic nerve cut. After optic nerve crush in the rat, c-JUN, JUN D, and KROX-24 appeared in a substantial number of RGCs after 24 h, had a maximal expression after 5 days, and strongly declined after 8 days. c-JUN and KROX-24 were completely absent after 22 days whereas JUN D was still present in a few rat RGCs. The number of CREB-labeled RGCs decreased after 5 days and had declined by 50% after 22 days. Expression of JUN B, c-FOS, FOS B could not be detected in rat RGCs after optic nerve crush. Our data demonstrate that the decrease of CREB and the increase of JUN and KROX-24 transcription factors precedes and parallels both the alteration of de novo protein synthesis and the axonal sprouting, which are long lasting in goldfish and transient in rat.

Animals↗
PubMed1994

Induction of c-Jun and suppression of CREB transcription factor proteins in axotomized neurons of substantia nigra and covariation with tyrosine hydroxylase.

In adult rats, the expression of transcription factor proteins c-Jun and CREB and their colocalization with tyrosine hydroxylase (TH) were investigated in neurons of the substantia nigra compacta (SNC) axotomized by stereotaxic unilateral transection of the medial forebrain bundle (MFB). Axotomized SNC neurons were identified by injection of the retrograde tracer horseradish-peroxidase-coupled-gold (HRP-gold) into the ipsilateral striatum 5 days prior to MFB transection. Nuclear c-Jun immunoreactivity (IR) appeared 36 h after MFB transection in SNC neurons, was maximal after 5 days, and declined after 10 days. c-Jun-IR was visible in HRP-gold-labeled SNC neurons, demonstrating that c-Jun is in fact expressed in axotomized neurons. The constitutively expressed CREB (calcium/cAMP response element-binding protein, syn. CREB-1) was present in apparently all neuronal and glial cells in the brains of untreated rats including those SNC neurons that coexpressed TH. Three days following MFB transection, the nuclear CREB-IR disappeared in the axotomized SNC neurons labeled by TH-IR and was almost completely absent after 20 days in this neuronal population. The TH-IR rapidly declined 5 days after MFB transection, and 10 and 100 days post-axotomy the number of TH-labeled neurons was reduced by 52 and 80%, respectively. During this period, the majority of surviving TH positive neurons coexpressed c-Jun but were immunonegative for CREB. Between 3 and 60 days following MFB transection, the number of CREB-labeled glial cell nuclei increased in the ipsilateral substantia nigra by about 80%. Concomitantly, expression of GFAP, a marker protein for astrocytes, was also enhanced whereas nuclear c-Jun-, JunD-, and c-Fos-IR did not change in glial cells. These findings demonstrate that c-Jun can be expressed in axotomized neurons during the absence of CREB and suggest a role of c-Jun in the transcriptional control of the TH gene.

Animals↗
PubMed1995

Serine 133-phosphorylated CREB induces transcription via a cooperative mechanism that may confer specificity to neurotrophin signals.

A mechanism has been characterized by which the transcription factor CREB regulates neurotrophin-induced gene expression. Whereas CREB can mediate calcium- or cyclic AMP-induced c-fos transcription independently of other promoter-bound transcription factors, CREB mediates NGF induction of c-fos transcription via a novel mechanism that appears to require a cooperative interaction with another transcription factor, the serum response factor. A similar transcriptional mechanism may explain how neurotrophins and growth factors induce distinct subsets of delayed response genes. Neurotrophins induce the phosphorylation of CREB at a key regulatory site, Serine 133, with prolonged kinetics that are distinct from the transient kinetics of CREB phosphorylation elicited by growth factors. These results indicate that CREB is a versatile transcription factor that activates transcription via distinct mechanisms in a stimulus-specific manner. In addition, by selectively activating delayed response genes, CREB may confer specificity to neurotrophin signals that promote the survival and differentiation of neurons.

Animals↗
PubMed2000

Regulation of CREB by moderate hypoxia in PC12 cells.

The mechanisms by which excitable cells adapt and respond to changes in O2 levels remain largely unknown. We have investigated the effect of hypoxia on the cyclic AMP response element binding protein (CREB) transcription factor. PC12 cells were exposed to moderate levels of hypoxia (5% O2) for various times between 20 min and 6 hr. We found that hypoxia rapidly and persistently induced ser133 phosphorylation of CREB. This effect was more robust than that produced by exposing PC12 cells to either forskolin, KCl, or NGF. This effect was not due to activation of any of the previously known CREB kinases, including PKA, CaMK, PKC, p70s6k, or MAPKAP kinase-2. Thus, hypoxia may induce activation of a novel CREB kinase. To test whether phosphorylation of CREB was associated with an activation of CRE-dependent gene expression, cells were transfected with wild type and mutated regions of the 5'-flanking region of the tyrosine hydroxylase (TH) gene fused to a CAT reporter gene. Mutation of the CRE element in a TH reporter gene reduced, but did not abolish, the effects of hypoxia on TH gene expression. However, hypoxia did not induce transactivation of a GAL4-luciferase reporter by a GAL4-CREB fusion protein. Thus, the mechanism by which hypoxia regulates CREB is distinct, and more complex, than that induced by forskolin, depolarization, or nerve growth factor.

Animals↗
PubMed2006

CREB and NF-kappaB transcription factors regulate sensitivity to excitotoxic and oxidative stress induced neuronal cell death.

1. Glutamate-NMDA receptor excitotoxicity and oxidative stress are two common mechanisms associated with most neurodegenerative diseases. We hypothesize that the vital state of neurons is regulated in part by two key transcription factors, CREB and NF-kappaB. To test this hypothesis we used hippocampal-entorhinal cortex slice cultures. 2. Glutamate neurotoxicity and oxidative stress neurotoxicity, using hydrogen peroxide (H(2)O(2)) are both associated with a decrease in CREB DNA binding and an increase in NF-kappaB DNA binding. 3. Agents that modulate CREB and NF-kappaB DNA-binding activity alter neurotoxicity. Rolipram, a phosphodiesterase IV inhibitor, increased CREB DNA binding activity and decreased toxicity, whereas TNFalpha, increased NF-kappaB DNA-binding activity and increased neurotoxicity to both glutamate and H(2)O(2). Ethanol decreased CREB and increased NF-kappaB DNA-binding activity and increased neurotoxicity to both glutamate and H(2)O(2). 4. Brain-derived neurotrophic factor (BDNF) is a transcriptionally regulated trophic factor whose expression follows sensitivity to toxicity suggesting it is one of the transcriptionally regulated factors that contributes to neuronal vitality secondary to the balance of CREB-NF-kappaB-activated transcription. Together these studies suggest that neurotoxicity through glutamate-NMDA receptors or oxidative stress is dependent upon CREB and NF-kappaB DNA transcription that regulates vitality of neurons.

Animals↗
PubMed2006

Nuclear Ca(++)-influx, Ca (++)/calmodulin-dependent protein kinase IV activity and CREB protein phosphorylation during post-hypoxic reoxygenation in neuronal nuclei of newborn piglets: the role of nitric oxide.

The present study tests the hypothesis that post-hypoxic reoxygenation results in an nitric oxide (NO)-mediated increase in nuclear Ca(++)-influx, increased calmodulin kinase (CaM kinase) IV activity, and increased Ser(133) phosphorylation of cyclic AMP response element binding (CREB) protein in neuronal nuclei of the cerebral cortex of newborn piglets. Piglets were divided into normoxic (Nx), hypoxic (Hx, FiO(2) = 0.07 for 1 h), hypoxic with 6 h reoxygenation (Hx + reox), and Hx + reox injected with 7-nitroindazole sodium salt (7-NINA), a nNOS inhibitor, immediately after hypoxia (Hx + 7-NINA). Cerebral tissue hypoxia was documented by ATP and phosphocreatine (PCr) levels. Nuclear Ca(++)-influx was determined using (45)Ca(++) and CaM kinase IV activity determined by (33)P-incorporation into syntide-2. Ser(133) phosphorylation of CREB protein was determined by Western blot analysis using a specific anti-phosphorylated Ser(133)-CREB protein antibody. ATP and PCr values in Hx, Hx + reox, and Hx + 7-NINA were significantly different from Nx (P < 0.05 versus Nx). Ca(++)-influx (pmoles/mg protein/min) was 3.79 +/- 0.91 in Nx; 11.81 +/- 2.54 in Hx (P < 0.05 versus Nx), 16.55 +/- 3.55 in Hx + reox (P < 0.05 versus Nx), and 12.40 +/- 2.93 in Hx + 7-NINA (P = NS versus Hx). CaM kinase IV activity (pmoles/mg protein/min) was 1,220 +/- 76 in Nx, 2,403 +/- 254 in Hx (P < 0.05 versus Nx), 1,971 +/- 147 in Hx + reox (P < 0.05 versus Hx), and 1,939 +/- 125 Hx + 7-NINA (P < 0.05 versus Hx). Ser(133) phosphorylated CREB protein expression (OD x mm(2)) was 87 +/- 2 in Nx, 203 +/- 24 in Hx (P < 0.05 versus Nx), 186 +/- 23 in Hx + reox (P < 0.05 Nx, P = NS versus Hx), and 128 +/- 10 in Hx + 7-NINA (P < 0.05 versus Hx and Hx + reox). The results show that post-Hx administration of 7-NINA prevents the increased nuclear Ca(++)-influx and CREB protein phosphorylation at Ser(133) during reox. We conclude that post-Hx increase in nuclear Ca(++)-influx leading to increased phosphorylation of CREB protein is mediated by NO derived from nNOS. However, hypoxia-induced increase in CaM Kinase IV activity decreased during the post-Hx reox. We propose that hypoxia-induced increase in CaM Kinase IV activity leads to increased phosphorylation of CREB protein and transcription of proapoptotic genes during post-Hx reox resulting in Hx neuronal death.

Adenosine Triphosphate↗
PubMed1990

Characterization of a bipartite activator domain in transcription factor CREB.

In this paper, we characterize a trans-activating region in CREB, termed alpha, that interacts cooperatively with the kinase A phosphorylation motif to stimulate transcription. The alpha region appears to be encoded by an alternate exon that is deleted in a CREB-related cDNA named delta CREB. Both proteins are expressed in eukaryotic cells, although the activity of CREB is 10-fold higher than that of delta CREB. Circular dichroism data on a synthetic "alpha peptide" combined with results from in vitro mutagenesis experiments support the hypothesis that the alpha region contains an amphipathic alpha helix whose structure is critical to CREB activity. We propose that phosphorylation by kinase A may stimulate CREB activity in part by modulating the structure of alpha and thus may stimulate its ability to interact with other proteins in the polymerase II complex.

Adrenal Gland Neoplasms↗
PubMed1996

Characterization and phosphorylation of CREB-like proteins in Aplysia central nervous system.

Studies in Aplysia californica indicate that cAMP-mediated gene expression is necessary for long-term facilitation, a correlate of long-term memory. It has been shown that blocking the expression of cAMP-inducible genes in sensory neurons impedes long-term facilitation without any effect on short-term facilitation. Specifically, blocking the binding of CREB-like proteins or inhibiting the expression of a cAMP-inducible gene, C[symbon: see text]EBP, impairs long-term facilitation. In this report, we show the presence of a family of CREB-like proteins in Aplysia CNS that specifically bind to the CRE sequence and cross-react with rat CREB antibodies. Similar to mammalian CREB proteins, Aplysia homologues interact with each other via leucine zipper domains. This interaction can be disrupted by peptides containing the CREB leucine zipper sequence. We demonstrate that a 43 kDa CREB-like protein present in CNS extracts can be phosphorylated in vitro by cAMP-dependent protein kinase A. Moreover, exposure of ganglia to serotonin (5-HT), a transmitter involved in long-term facilitation, increases the phosphorylation of this protein. This biochemical data further supports the involvement of CREB-like proteins in memory storage.

Animals↗