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PubMed2003

Differences in basal levels of CREB and NPY in nucleus accumbens regions between C57BL/6 and DBA/2 mice differing in inborn alcohol drinking behavior.

An increasing body of evidence suggests that genetic factors play a role in alcohol drinking behaviors. C57BL/6J (C57) mice innately consume larger amounts of alcohol compared to that consumed by DBA/2J (DBA) mice. Furthermore, alterations in cAMP-responsive element binding (CREB) protein function in the brain have been implicated in alcohol drinking behaviors. The present investigation examined innate expression and phosphorylation of CREB in various brain structures of C57 and DBA mice. It was found that CREB expression and phosphorylation was lower, specifically in the shell structure of the nucleus accumbens, in C57 mice compared to that in DBA mice. CREB expression and phosphorylation were similar in other brain regions such as the nucleus accumbens core and the cortical, amygdaloid, hippocampal, and striatal structures of C57 and DBA mice. The expression of a cAMP-inducible gene, neuropeptide Y (NPY), was also investigated in the nucleus accumbens region of C57 and DBA mice. It was found that in C57 mice, NPY protein levels were lower in the shell but not in the core structure of the nucleus accumbens compared to that in DBA mice. It was also found that C57 mice are not innately anxious, but they consume larger amounts of alcohol than do DBA mice. Because the shell structure of the nucleus accumbens has been implicated in reward mechanisms of alcohol, it is possible that lower CREB function in this brain structure may be in part associated with the excessive alcohol drinking behavior of C57 mice.

Alcohol Drinking↗
PubMed1993

Bacterial expression and characterization of the CREB bZip module: circular dichroism and 2D 1H-NMR studies.

In this paper we describe the expression and purification from bacteria of the recombinant basic leucine zipper (bZip) domain of the cAMP response element binding protein, CREB327. The bZip peptide, CREB259-327, purified to near homogeneity, maintains the sequence-specific CRE site recognition demonstrated by in vitro competition assays. Alkylation of the three cysteine residues of CREB259-327 was employed to prevent aggregation of the peptide due to cysteine oxidation. The Kd of the purified native and modified CREB259-327 for the CRE site was determined by gel retardation assays to be on the order of 10(-7) M. We employed CD spectroscopy to study the folding properties of the native and modified CREB259-327. The CD analyses of the native/modified CREB259-327 peptide demonstrated a 20% increase in the alpha-helical content upon binding to the cAMP response-element. Only a 5% increase in the alpha-helical content of CREB259-327 is observed upon binding to the AP-1 site. This observation contrasts with CREB from the GCN4 protein (Weiss, M.A., et al., 1990, Nature 347, 575-578). In addition, the two-dimensional (2D) 1H-NMR studies of the bZip CREB peptide further support the distinct features of the CREB protein, in comparison to GCN4. Analysis by CD and 2D NMR of the dimerization domain of CREB suggests that the distinct DNA binding characteristics of CREB reside in the basic portion of the bZip module.

Amino Acid Sequence↗
PubMed1995

Phosphorylation of CREB by CaM-kinase IV activated by CaM-kinase IV kinase.

Previous reports have shown that CaM-kinase IV can phosphorylate the transcription factor CREB in vitro on Ser133. Furthermore, transfected CaM-kinase IV can activate CREB-dependent transcription, but at a lower efficiency than the cAMP-kinase. In this paper we examine the kinetics and site-specificity of CREB phosphorylation in vitro by CaM-kinase IV after its phosphorylation and activation by a newly discovered brain CaM-kinase IV kinase. Our results show that activated CaM-kinase IV has the same Km (1-5 microM) for CREB phosphorylation, but the Vmax is about 30-fold higher than with non-activated CaM-kinase IV. Activated CaM-kinase IV still shows specificity for phosphorylation of Ser133, the site necessary for transactivation by CREB. It is likely that the lower efficiency of transcriptional activation by transfected CaM-kinase IV in previous studies was due to the fact that the CaM-kinase IV was not activated by CaM-kinase IV kinase.

Amino Acid Sequence↗
PubMed1997

Elevated amyloid beta protein(1-40) level induces CREB phosphorylation at serine-133 via p44/42 MAP kinase (Erk1/2)-dependent pathway in rat pheochromocytoma PC12 cells.

The deposition of amyloid beta protein (A beta) in the cerebral cortex is the pathological characteristic of Alzheimer's disease (AD), and patients with AD suffer from progressive memory loss. Transgenic experiments have revealed that long-term memory is dependent on cyclic AMP-response element binding protein, CREB. CREB phosphorylation at serine-133 is essential for its transcriptional activity. Here we demonstrated that A beta(1-40), at a concentration more than 1 microM, induced CREB phosphorylation at serine-133 in rat pheochromocytoma PC12 cells. A beta(1-40) induced phosphorylation of p44 and p42 MAP kinases (Erk1 and Erk2) at tyrosine-204, and PD98059, a MEK1 inhibitor, inhibited A beta(1-40)-induced CREB phosphorylation at serine-133. We conclude that elevated A beta(1-40) level induces CREB phosphorylation at serine-133 via p44/42 MAP kinase-dependent pathway.

Amyloid beta-Peptides↗
PubMed2000

Tip60 inhibits activation of CREB protein by protein kinase A.

We have previously identified a cDNA encoding a cellular protein, Tip60 (Tat interactive protein, 60 kDa), that specifically interacts with the Tat (transactivating transcriptional regulator) protein of the human immunodeficiency virus-1 (HIV-1). In this report, we have characterized cellular Tip and find that it is a 60 kDa nuclear protein expressed in a wide variety of differentiated cell lines from insects to man. To identify cellular functions of Tip, we have assayed the effects of Tip on cellular pathways that Tat has been reported to affect. Overexpression of Tip results in an almost complete block in activation of a Gal4-CREB (cAMP response element binding protein) fusion protein by cyclic AMP dependent protein kinase A (PKA). This inhibition appears to be mediated through direct interaction of Tip and CREB, since Tip directly binds to CREB protein in vitro. We show that amino acid substitutions of two conserved amino acids found in the putative acetyl coenzyme A binding motif of Tip completely abolishes the histone acetyltransferase (HAT) activity of recombinant Tip. Inhibition of CREB activation by Tip is not diminished in a HAT negative Tip mutant, indicating that Tip can negatively regulate gene expression independent of HAT activity. Recently, Tip has also been shown to be a transcriptional coactivator of nuclear hormone receptors; therefore, Tip can both activate transcription factors of one signaling pathway (nuclear hormone receptors) and bind to a different transcription factor (CREB) and inhibit activation of another signaling pathway.

Acetyltransferases↗
PubMed1999

Gene regulation mediated by interaction between HTLV-1 promoter elements and transcription factors Tax and CREB.

In this work we examine the role of three genetic control components in the regulation of HTLV-1 transcription: cyclic AMP-responsive element (CRE)-binding protein (CREB), the HTLV-1 trans-activator Tax, and the three Tax-responsive elements (TREs). We demonstrate that the in vivo efficiency of the HTLV-1 promoter basal expression in cell culture depends on the spacing between the three TRE elements, located at the HTLV-1 LTR (long terminal repeat), whereas the level of transcription activation mediated by Tax is affected by the number of TREs. In the presence of only one TRE, the enhancement of expression by Tax is affected by the distance between the single TRE and the transcription start site. Following CREB binding to the LTR, additional DNase I hypersensitive sites are generated in the region between the two distal TREs (I and II), while in the presence of Tax, such sites are generated also in the region between TREs II and III. Neither cooperative binding of CREB to the TREs nor preferential binding of CREB to a particular TRE was observed. Tax binding to the CREB/TRE complex does not change the DNase I protection pattern. Taken together, these results suggest that the basal CREB-mediated transcription is determined by the number and the position of the viral TREs relative to each other. Tax protein stabilizes the protein/DNA complex and suppresses the spacing limitations, probably by bridging between the CREB/TRE complexes and the basal initiation transcription complex.

3T3 Cells↗
PubMed1999

CREB: a message to remember.

The prevailing hypothesis for the formation of long-term memory (LTM) is that introduction of a memory item alters the pattern of existing neuronal connectivity to form a neuronal network that will subserve the information for long-term storage. Modulation of synaptic efficacy is induced by changes in synaptic transmission within selected synapses or alteration in synaptic contacts. These changes are in turn supported by molecules that underlie transmission or synaptic remodeling. It is suggested that modulation of gene expression is needed for LTM formation to overcome the relative short lifetime of proteins in neurons (as compared with enduring memory). One of the most salient results consonant with this hypothesis is that the transcription factor cAMP response element binding (CREB) is involved in the formation of memory in organisms with diverse phylogenetic background from mollusks to mammals. CREB subserves the formation of memories of various types of tasks that utilize different brain structures. Circumstantial evidence is available suggesting that CREB regulates the transcription of genes that subserve LTM. The present review is focused on the CREB protein, its role in memory formation and considers mechanistic models pertaining to CREB action in modulating neuronal networks that underlie LTM.

Animals↗
PubMed1999

Novel variants in the promoter region of the CREB gene in schizophrenic patients.

Cyclic AMP-responsive element-binding protein (CREB) is one of the messenger molecules involved in intracellular signal transduction pathways used by most dopamine and serotonin receptor subtypes. In addition, CREB stimulates the expression of a number of genes, alterations in the expression of which may be associated with schizophrenia. The promoter region of the human CREB gene was therefore analyzed to identify genetic variants that may lead to the modification of CREB expression and contribute to schizophrenia. Eighty unrelated schizophrenics and 100 healthy controls were screened for genetic variants of the CREB gene by SSCP analysis, followed by direct sequencing of PCR products. Two novel variants (-933T-->C and -413G-->A) were found only in schizophrenics. A patient with the -933T-->C variant had unusual clinical characteristics in addition to typical schizophrenic symptoms.

Cyclic AMP Response Element-Binding Protein↗
PubMed2005

Activated cyclic AMP-response element binding protein (CREB) is expressed in a myelin-associated protein in chick.

Cyclic AMP response element (CRE) is a specific DNA sequence, which mediates transcriptional activation in the response to the cyclic AMP-activated and protein kinase A dependent signaling pathway. In the present study, phosphorylated CRE binding protein (CREB) immunoreactivity was mainly localized in the white matter of chick central nervous system (CNS). We have further confirmed the specificity of phospho-CREB immunoreaction in myelin using demyelinated optic nerve induced by lysophophatidylcholine (LPC), which is known to produce demyelination with little axonal damage. Double immunofluorescent analyses with myelin basic protein (MBP) and transferrin binding protein (TfBP), oligodendrocyte marker showed that phospho-CREB recognized a myelin-related protein in chick. Immunoblot analyses showed that phospho-CREB recognized a protein with molecular weights of approximately 70 kDa. Our data suggest that the antigen recognized by phospho-CREB is a myelin-associated protein in the chick CNS.

Animals↗
PubMed2006

Effect of antisense FosB and CREB on the expression of prodynorphin gene in rats with levodopa-induced dyskinesias.

The effects of antisense FosB and CREB intra-striatum injection on the expression of prodynorphin (PDyn) gene in striatal neurons of Levodopa-induced dyskinesias (LID) rats with Parkinson disease (PD) were explored. PD model in rats was established by 6-OHDA microinjection stereotaxically. The rats were treated with chronic intermittent Levodopa celiac injection for 28 days to get the LID rats. Antisense FosB and cAMP response element-binding protein (CREB) were injected into striatum of all rats respectively. In situ hybridization was used to measure the changes in the expression of PDyn mRNA in striatum and behavior changes were observed. The results showed after administration of antisense FosB, abnormal involuntary movement (AIM) was decreased and the expression of PDyn mRNA in striatum was increased in LID rats as compared with sense FosB group (P<0.01, respectively). As compared with the control group, the expression of PDyn mRNA in striatum was decreased by antisense CREB-treated LID group (P<0.01) and compared with sense CREB treated LID group, antisense CREB-treated LID group showed no changes in AIM scores and the expressions of PDyn mRNA (both P>0.05). In conclusion, FosB protein, which replaced the CREG, could regulate the expression of PDyn mRNA and play critical role in the pathogenesis of LID.

Animals↗
PubMed1992

Transcriptional attenuation following cAMP induction requires PP-1-mediated dephosphorylation of CREB.

We have examined the mechanism by which the transcriptional activity of the cAMP-responsive factor CREB is attenuated following induction with forskolin. Metabolic labeling studies reveal that, after an initial burst of phosphorylation in response to cAMP, CREB is dephosphorylated and transcription of the cAMP-responsive somatostatin gene is correspondingly reduced. The phosphatase inhibitor 1 protein and okadaic acid both prevented the dephosphorylation of CREB at Ser-133 in PC12 cells and also augmented the transcriptional response to cAMP. Of the four Ser/Thr phosphatases described to date, only PP-1 appears to be similarly inhibited by these agents. As PP-1 specifically dephosphorylates CREB at Ser-133 and inhibits cAMP-dependent transcription, we propose that this phosphatase is the major regulator of CREB activity in cAMP-responsive cells.

Cyclic AMP↗
PubMed1995

Time course of phosphorylated CREB and Fos-like immunoreactivity in the hypothalamic supraoptic nucleus after salt loading.

Phosphorylation of the cAMP response element binding protein (CREB) precedes the induction of immediate early gene expression. Using antibodies that distinguish CREB from phosphorylated CREB (PCREB), we studied the appearance of PCREB-like immunoreactivity (PCREB-LI) and Fos-LI in the hypothalamic supraoptic nucleus (SON) of rats treated with hypertonic or normal saline and uninjected controls. Fifteen minutes after injection, increased numbers of PCREB-LI cells were seen in both normal and hypertonic saline-treated rats as compared with uninjected controls. Forty-five minutes after injection, levels of c-fos mRNA in the SON were elevated in hypertonic saline-treated rats as compared with normal saline-treated rats, and were minimally detectable in uninjected rats. At this time period, the hypertonic saline-treated rats showed increased number of Fos-LI cells in the SON, whereas normal saline-treated rats showed little or no Fos-LI cells. The discrepancy between levels of PCREB-LI and c-fos mRNA suggests that injection of hypertonic saline may activate additional transcriptional factors besides CREB. The lack of Fos-LI in the presence of modest increases in c-fos mRNA in normal saline-treated rats implies that levels of c-fos mRNA must exceed a threshold before increases in Fos-LI cells are detectable by immunostaining of the SON. Such a threshold might permit neuronal cells to activate diverse genes, through phosphorylation of CREB, without inducing the constellation of Fos-responsive genes.

Animals↗
PubMed1994

The transcription factor CREB is not phosphorylated at serine 133 in axotomized neurons: implications for the expression of AP-1 proteins.

The present study has investigated whether nerve fiber transection alters the phosphorylation of serine at position 133 (Ser133) of the transcription factor CREB (phosphoCREB). Activation of CREB by phosphorylation has a major function in the control of gene transcription. PhosphoCREB was visualized by antisera that specifically react with an epitope comprising the phosphorylated Ser133 of CREB as well as of CREM and ATF1 proteins. In untreated rats, nuclear immunoreactivity (IR) of phosphoCREB was consistently visible, e.g. in the cortex, thalamic and hypothalamic compartments and central termination areas of primary somatosensory afferents. Transection of peripheral (sciatic nerve), cranial (hypoglossal and facial nerve) and central (medial forebrain bundle and mammillo-thalamic tract) nerve fibers did not increase phosphoCREB-IR in the axotomized neurons between 5 min and 30 days post-axotomy. In contrast, phosphoCREB-IR appeared after 24 h in glial cells adjacent to the axotomized motoneurons and persisted up to 4 weeks. This increase in glial phosphoCREB-IR was paralleled by enhanced expression of the CREB protein itself. Between 20 min and 24 h following sciatic nerve transection, the number of phosphoCREB labeled nuclei also increased in neurons of the ipsilateral superficial dorsal horn of lumbar L3-L5 spinal cord segments. These data suggest that phosphorylation of Ser133 in CREB/CREM/ATF1 proteins is not involved in the transcriptional control of early-response genes such as c-jun in axotomized neurons following nerve transection. This is in contrast to the reported phosphorylation of CREB and its trans-acting effects on immediate-early genes such as c-fos after transynaptic neuronal excitation.

Afferent Pathways↗
PubMed1992

The transcription factor CREB, but not immediate-early gene encoded proteins, is expressed in activated microglia of lumbar spinal cord following sciatic nerve transection in the rat.

Expression of CREB, JUN, FOS and KROX-24 proteins was investigated in glial cells of the lumbar spinal cord. In untreated rats, CREB, c-JUN and JUN D were present in glial cells of the ventral and dorsal horn. Following sciatic nerve transection, the number of CREB immunoreactive glial cells increased in both the ipsilateral ventral and dorsal horns between 24 h and 48 h, reached a maximum after 5 days and returned to control levels after 20 days. Counterstaining with Cresyl violet, a general stain of cells, revealed that the increase of CREB positive glial cells was congruent with the increase of the number of glial cells. Staining with GFAP, a marker for astrocytes, showed an increase in intensity of labelling but no change in number of GFAP labelled cells. This indicates a constitutive expression of CREB in activated microglia. The number of glial cells labelled by c-JUN and JUN D did not change, and glial cells were not labelled by FOS and KROX-24 proteins following sciatic nerve transection. These findings demonstrate that proliferation and differentiation of glial cells in vivo can occur in absence of JUN, FOS and KROX proteins.

Animals↗
PubMedDate not supplied

Overexpression and purification of transcriptionally competent CREB from a recombinant baculovirus.

Signal transduction and viral stimulatory pathways converge ultimately at the level of transcriptional activation to influence the expression of a variety of cellular genes in response to environmental stimuli and developmental signals. Recent studies have implicated the cyclic AMP-responsive element-binding protein (CREB) to be involved in mediating transcriptional activation in response to multiple varied stimuli, including (1) stimulation of the protein kinase A signal transduction pathway; (2) membrane depolarization and increases in intracellular calcium; and (3) viral induced gene expression. In order to study the structure and functional mechanisms of CREB actions in these systems, full-length CREB-327 was expressed in Spodoptera frugiperda (Sf9) cells with the baculovirus expression vector system. The expressed CREB, which is phosphorylated and localized in the nucleus, is capable of enhancing the transcription of a reporter gene containing the CRE sequence in a cell-free transcription assay. Approximately 12.5 mg of purified CREB per liter of infected Sf9 cell culture can be obtained. These large amounts of purified protein will facilitate studies of the structure and functions of this important transcriptional regulatory protein.

Animals↗
PubMed2004

Endothelin-1 promotes phosphorylation of CREB transcription factor in primary cultures of neonatal rat cardiac myocytes: implications for the regulation of c-jun expression.

Cardiac myocyte hypertrophy is associated with an increase in expression of immediate early genes (e.g. c-jun) via activation of pre-existing transcription factors. The activity of CREB transcription factor is regulated through phosphorylation of Ser-133 by one of several protein kinases (e.g. protein kinase A (PKA), p90 ribosomal S6 kinases (RSKs) and the related kinase, MSK1). A cell-permeable form of cAMP, hypertrophic agonists (endothelin-1 (ET-1), phenylephrine (PE)) and hyperosmotic shock all promoted phosphorylation of CREB(Ser-133) in rat neonatal cardiac myocytes. The response to endothelin-1 required the extracellular signal-regulated kinase cascade which stimulates both RSKs and MSK1. Phosphorylation of CREB(Ser-133) in response to ET-1 was not associated with any increase in DNA binding to a consensus cAMP-response element (CRE). The rat c-jun promoter contains elements which may bind either c-Jun/ATF2 or CREB/ATF1 dimers. Using extracts from rat cardiac myocytes, we identified at least two complexes which bind to the most proximal of these elements, one of which contained CREB and the other c-Jun. Thus, phosphorylation and activation of CREB in cardiac myocytes may be effected by a range of different stimuli to influence the expression of immediate early genes such as c-jun.

Animals↗
PubMed2005

CREB phosphorylation following hypoxia and ischemia in striatum of newborn piglets: possible role of dopamine.

The goal of the present study was to determine the effects of hypoxia and ischemia and the role of dopamine on phosphorylation of cAMP response element binding protein (CREB) in striatum of newborn piglets. Piglets, with and without prior injection of alpha-methyl-p-tyrosine (AMT), an inhibitor of dopamine (DA) synthesis, were subjected to 1 h of hypoxia (decreased inspired oxygen pressure, FiO2, from 21 to 6%) or 1 h of ischemia (ligation of both carotid arteries and hemorrhage to reduce the systemic arterial pressure to about 40 mmHg), followed by 2 h recovery. Microvascular oxygen pressure in the cortex (pCO2) was measured by quenching of phosphorescence. Extracellular DA was determined by in vivo microdialysis. Striatal levels of phosphorylated CREB (pCREB) and total CREB were determined by Western blots. In sham-operated animals, pCO2 was 49.7 +/- 8.2 mmHg. During hypoxia and ischemia, pCO2 decreased to 6.3 +/- 1.8 mmHg and 10.2 +/- 2.7 mmHg, respectively. There was statistical difference in the level of extracellular DA during hypoxia versus ischemia. At the end of ischemia and hypoxia, the levels of DA were 96 x 10(3) +/- 24 x 10(3)% and 26 x 10(3) +/- 12 x 10(3)% of control, respectively. The pCREB measured after 2 h recovery was not changed after hypoxia but was decreased to 47.8 +/- 24% of control after ischemia. Depletion of endogenous DA abolished the ischemia-induced decrease in pCREB level. Total CREB did not change after either condition. It can be concluded that observed decreases of CREB phosphorylation following ischemia can be at least partially due to the high extracellular DA level.

Animals↗
PubMed2005

Simvastatin inhibits NOR-1 expression induced by hyperlipemia by interfering with CREB activation.

OBJECTIVE: Our aim was to investigate whether neuron-derived orphan receptor-1 (NOR-1), an early gene induced by low density lipoproteins (LDL) in vascular smooth muscle cells (VSMC), is regulated by statins. METHODS: NOR-1 expression was analyzed in human VSMC in culture and in vivo in the aorta of diet-induced hyperlipemic pigs by RT-PCR and real-time PCR. [3H]Thymidine incorporation was used as an index of DNA synthesis. NOR-1 promoter activity was analyzed using a luciferase reporter system. Cyclic AMP response element binding protein (CREB) binding was assessed by EMSA and ELISA and CREB activation (phosphorylation in Ser133) by Western blotting. RESULTS: Simvastatin inhibited NOR-1 expression induced by LDL in VSMC and by hypercholesterolemia in the abdominal aorta of hyperlipemic pigs. The inhibition of the isoprenylation of geranylgeranylated proteins by simvastatin was key in both NOR-1 up-regulation and DNA synthesis induced by LDL. Inhibitors of RhoA (toxin B and exotoxin C3) and ROCK (Y-27632) mimicked the effect of simvastatin on NOR-1. Similarly both simvastatin treatment and cells transfected with a RhoA dominant-negative (RhoAT19N) showed inhibition of LDL-induced NOR-1 promoter activity. These effects were associated to the interference of the activation of CREB, a key transcription factor involved in NOR-1 induction. Finally, simvastatin prevented LDL induction of a reporter construct containing four consensus CRE and inhibited the expression of SMemb (a marker for dedifferentiated VSMC) dependent on CREB. CONCLUSIONS: NOR-1 is a target for simvastatin in the vascular wall. We identified NOR-1 and CREB as key transcription factors mediating the effect of statins on VSMC proliferation through a mechanism dependent on RhoA/ROCK.

Animals↗