Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “CREB”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 865 records · Page 48Linked to original sources
PubMed1997

Construction of a 1.2-Mb contig surrounding, and molecular analysis of, the human CREB-binding protein (CBP/CREBBP) gene on chromosome 16p13.3.

In the interest of cloning and analyzing the genes responsible for two very different diseases, the Rubinstein-Taybi syndrome (RTS) and acute myeloid leukemia (AML) associated with the somatic translocation t(8;16)(p11;p13.3), we constructed a high-resolution restriction map of contiguous cosmids (contig) covering 1.2 Mb of chromosome 16p13.3. By fluorescence in situ hybridization and Southern blot analysis, we assigned all tested RTS and t(8;16) translocation breakpoints to a 100-kb region. We have previously reported exact physical locations of these 16p breakpoints, which all disrupt one gene we mapped to this interval: the CREB-binding protein (CBP or CREBBP) gene. Intriguingly, mutations in the CBP gene are responsible for RTS as well as the t(8;16)-associated AML. CBP functions as an integrator in the assembly of various multiprotein regulatory complexes and is thus necessary for transcription in a broad range of transduction pathways. We report here the cloning, physical mapping, characterization, and full cDNA nucleotide sequence of the human CBP gene.

Amino Acid Sequence↗
PubMed1999

Structural analyses of CREB-CBP transcriptional activator-coactivator complexes by NMR spectroscopy: implications for mapping the boundaries of structural domains.

A number of signal-dependent and development-specific transcription factors recruit CREB binding protein (CBP) for their transactivation function. The KIX domain of CBP is a common docking site for many of these transcription factors. We recently determined the solution structure of the KIX domain complexed to one of its targets, the Ser133-phosphorylated kinase inducible transactivation domain (pKID) of the cyclic AMP response element binding protein. The NMR studies have now been extended to a slightly longer KIX construct that, unlike the original KIX construct, is readily amenable to structural analysis in both the free and pKID-bound forms. This addition of six residues (KRRSRL) to the C terminus of the original construct elongates the C-terminal alpha3 helix of KIX by about eight residues. On the basis of the NMR structure of the original KIX construct, residues in the extended helix are predicted to be solvent exposed and thus are not expected to contribute to the hydrophobic core of the domain. Their role appears to be in the stabilization of the alpha3 helix through favorable electrostatic interactions with the helix dipole, which in turn confers stability on the core of the KIX domain. These results have important implications for the identification of novel protein domain boundaries. Chemical shift perturbation mapping firmly establishes a similar mode of pKID binding to the longer KIX construct and rules out any additional intermolecular interactions between residues in the C-terminal extension and pKID.

Acetyltransferases↗
PubMed2005

The histone chaperone SET/TAF-Ibeta interacts functionally with the CREB-binding protein.

The oncoprotein SET/TAF-Ibeta is a histone chaperone which is involved in cell-cycle control and chromatin remodeling. Confocal laser scanning microscopy reveals that SET is localized in distinct foci of variable size throughout the nucleoplasm of interphase cells. We report here that SET interacts directly with the acetyltransferase CREB-binding protein (CBP) and enhances the transactivation potential of the transcription coactivator. Our data suggest that the histone chaperone SET regulates the CBP-mediated transcription and may indicate a general principle by which transcriptional regulators cooperate with histone chaperones for gene activation.

Biotinylation↗
PubMed2006

An essential GT motif in the lamin A promoter mediates activation by CREB-binding protein.

Lamin A is an important component of nuclear architecture in mammalian cells. Mutations in the human lamin A gene lead to highly degenerative disorders that affect specific tissues. In studies directed towards understanding the mode of regulation of the lamin A promoter, we have identified an essential GT motif at -55 position by reporter gene assays and mutational analysis. Binding of this sequence to Sp transcription factors has been observed in electrophoretic mobility shift assays and by chromatin immunoprecipitation studies. Further functional analysis by co-expression of recombinant proteins and ChIP assays has shown an important regulatory role for CREB-binding protein in promoter activation, which is mediated by the GT motif.

Animals↗
PubMed2004

Targeting CREB-binding protein (CBP) loss of function as a therapeutic strategy in neurological disorders.

Histone acetylation/deacetylation is a master regulation of gene expression. Among the enzymes involved in this process, the CREB-binding protein (CBP) displays important functions during central nervous system development. Increasing evidence shows that CBP function is altered during neurodegenerative processes. CBP loss of function has now been reported in several diseases characterized by neurological disorders such as the Rubinstein-Taybi syndrome or polyglutamine-related pathologies (Huntington's disease). Our recent work suggests that CBP loss of function could also be involved in Alzheimer's disease and amyotrophic lateral sclerosis. In a simplified apoptotic model of primary neurons, we described CBP as a substrate of apoptotic caspases, an alternative to its classical proteasomal degradation. In these neuronal death contexts, histone acetylation levels were decreased as well. Altogether, these data point to a central role of CBP loss of function during neurodegeneration. In order to restore proper acetylation levels, a proposed therapeutic strategy relies on HDAC inhibition. Nevertheless, this approach lacks of specificity. Therefore new drugs targeted at counteracting CBP loss of function could stand as a valid therapeutic approach in neurodegenerative disorders. The challenge will be to respect the fine-tuning between cellular HAT/HDAC activities.

Animals↗
PubMed2005

Thyrotropin-releasing hormone (TRH) specific interaction between amino terminus of P-Lim and CREB binding protein (CBP).

P-Lim (Lhx3a) is a LIM homeodomain transcription factor essential for pituitary development and motor neuron specification in mice. The Lhx3 gene encodes two isoforms, which differ in their amino (N) termini, Lhx3a and 3b. The P-Lim DNA binding site on the glycoprotein hormone alpha subunit (alpha-GSU) gene promoter is conserved in mammals. P-Lim plays a pivotal role in mediating thyrotropin-releasing hormone (TRH) signaling by binding CREB binding protein (CBP), as we have reported previously. Here, we demonstrate that P-Lim (Lhx3a) but not Lhx3b can mediate TRH signaling and bind to CBP. Moreover, TRH specifically induces P-Lim-CBP binding through the N-termini of P-Lim. We also found that the protein kinase C (PKC) phosphorylation site within the N-terminus of P-Lim is responsible for the P-Lim-CBP binding suggesting that the TRH signaling pathway phosphorylates P-Lim. These studies have elucidated the molecular mechanism by which TRH stimulates alpha-GSU gene expression.

Animals↗
PubMed2004

The calcium-responsive transactivator recruits CREB binding protein to nuclear bodies.

The calcium-responsive transactivator (CREST) is required for the normal development of neuronal dendritic trees. Here we report that CREST is localized to sub-nuclear structures in the rat neuroendocrine pheochromocytoma PC12 cells. A yellow fluorescence protein-CREST fusion protein was expressed in HEK 293 and PC12 cells and the recombinant protein was exclusively targeted to nuclear bodies. A similar result was obtained with a Flag-tagged CREST. Deleting the N-terminal 148 or the C-terminal 79 amino acid sequences had no effect on targeting, whereas removing 164 amino acid residues from the C-terminus abolished nuclear body localization. We found that CREST did not co-localize with promyelocytic leukaemia oncoprotein (PML) body and was not targeted to PML bodies. Overexpression of CREST markedly increased the number of nuclear bodies positive for the histone acetyltransferase CREB binding protein (CBP). Double immunofluorescence staining of Flag-CREST and CBP suggested that CREST and CBP had a high degree of co-localization within the nuclear bodies. Deletion of the CBP binding domain of CREST inhibited the recruitment of CBP to CREST nuclear bodies. These results suggest that CBP recruitment to nuclear bodies by CREST may play an important role in CREST-mediated calcium-responsive transactivation, and CREST nuclear body may function as an assembly site for activators/co-activators in gene transcription control.

Alcohol Oxidoreductases↗
PubMed2005

Minor expression of fascin-1 gene (FSCN1) in NTera2 cells depleted of CREB-binding protein.

CREB-binding protein (CBP) is a transcriptional coactivator whose mutations may cause a generalized perturbation of gene expression. We silenced the CBP gene in NT2 neuronal precursor cells by RNA interference. Hybridization experiments on 1.2K human cDNA microarrays showed that the FSCN1 gene, encoding for fascin-1 protein, was clearly less expressed in CBP-depleted cells than in controls. This reduction was confirmed by Real Time PCR and Western blotting assays. We also analyzed FSCN1 expression profile during NT2 neuronal differentiation induced by retinoic acid (RA), showing that FSCN1 was up-regulated during neurogenesis. This mRNA increasing suggests the importance of fascin-1 in the formation of mature neurons, in accordance with its actin-bundling function and its localization in neurites and neuronal growth cones. The lower amount of FSCN1 transcript in the absence of the CBP factor was also established in RA-treated cells. In conclusion, this research supports FSCN1 as a novel marker of NT2 neuronal differentiation and the possible role of CBP in its regulation.

CREB-Binding Protein↗
PubMed2006

Homocysteine regulates expression of Herp by DNA methylation involving the AARE and CREB binding sites.

Herp (homocysteine-induced endoplasmic reticulum protein) is an ER-resident membrane protein, which has a ubiquitin-like domain at its N-terminus. Expression of Herp protein is up-regulated in response to ER stress, including homocysteine. Herp stabilizes neuronal Ca(2+) homeostasis and is involved in improving the balance of the folding capacity and protein loading in the ER. In patients with alcoholism, we observed a significant decrease in Herp mRNA expression, and an increase of Herp promoter DNA methylation, which was associated with elevated homocysteine levels. Therefore, we studied the mechanism of Herp CpG islands regulation by luciferase assays and mRNA analysis in neuronal SH-SY5Y (human neuroblastoma cell line) and HEK 293T (human embryonic kidney 293T) cells. Acute homocysteine treatment caused transient demethylation of the Herp promoter and an increase in Herp mRNA level. Global DNA methylation was increased over the following 48 h period. We identified the transcription factor binding site AARE (amino acid response element) by mutational analysis involved in Herp induction in SH-SY5Y cells, and the more significant role of the CREB binding site (cyclic AMP response element-binding protein) compared to AARE in HEK 293T cells. Stimulation with SAM (S-adenosyl methionine) and homocysteine led to an increase in Herp promoter methylation, which correlated to an acute decrease in luciferase expression in SAM, but not in homocysteine stimulated cells. Complete methylation of the CpG islands resulted in suppressed gene expression.

Base Sequence↗
PubMed2002

Age-related changes in CREB binding protein immunoreactivity in the cerebral cortex and hippocampus of rats.

Although the role of cAMP-response-element-binding protein (CREB) binding protein (CBP) in the neuroprotective mechanisms has been the focus of many studies, very little is known about the expression or function of CBP in aged brains. We have therefore examined age-related changes in CBP expression in the cerebral cortex and hippocampus with an immunohistochemical technique. In the cerebral cortex, the distribution patterns were not different between adult and aged groups, but the staining intensity of CBP was significantly decreased in aged rats. In the hippocampus, a distinct immunoreactivity pattern was observed in the CA1-3 areas and dentate gyrus. CBP immunoreactivity was significantly deceased in the pyramidal layer of CA1-3 regions in aged hippocampus. In the dentate gyrus of aged rats, significant decreases were also found in the granule cell layer and polymorphic layer. The first demonstration of age-related decreases in CBP expression in the cerebral cortex and hippocampus may provide useful data for investigating the pathogenesis of age-related neurodegenerative diseases and depression.

Aging↗
PubMed1999

Distribution of CREB-binding protein immunoreactivity in the adult rat brain.

We demonstrate the expression of the co-activator CREB-binding protein (CBP) in the nuclei of a large number of neurons and glial structures in the rat brain and spinal cord. Immunoblotting of nuclear extracts revealed a single band at 265 kDa, the size of CBP. We found that CBP immunoreactivity was localized to cholecystokinin mRNA-expressing neurons in the hippocampus and the thalamus, suggesting that CBP may be involved in long-term memory and modulation of cortical activity. However, CBP-labeling was not ubiquitous, and many brain regions, including several mesencephalic and diencephalic nuclei, showed sparse labeling. Further, the number of neurons displaying intense CBP-labeling varied across animals in some regions, e.g., the hippocampus and the amygdala. Since competition for limited amounts of CBP and CBP-related molecules has been shown to be important for the integration of intracellular signaling pathways with transcriptional regulation, the present results suggest that varying endogenous levels of CBP in post-mitotic neurons is an important parameter in neuronal transcriptional regulation.

Acetyltransferases↗
PubMed2004

Disease-related potential of mutations in transcriptional cofactors CREB-binding protein and p300 in leukemias.

CREB-binding protein (CBP) and highly related p300 protein are transcriptional co-activators that play an essential role in chromatin remodeling through histone acetyltransferase activity and interaction with other transcriptional regulators. In this study, various hematological malignancies, including nine cell lines and 45 clinical samples (32 acute myeloid leukemias (AML), nine acute lymphoblastic leukemias (ALL), two cases of myelodysplastic syndrome (MDS), one multiple myeloma, and one chronic myelogenous leukemia in blast crisis), were examined to ask whether mutation of the CBP and p300 genes could be involved in leukemogenesis. The answer was approached by employing the reverse transcription-polymerase chain reaction and single-strand conformation polymorphism (RT-PCR/SSCP) technique and subsequent sequence analysis. A T-lymphoblastic cell line, CEM had an in-frame 21-base-pair deletion within the bromodomain of its p300 cDNA. Genomic DNA analysis revealed aberrant splicing caused by mutation of the acceptor site of intron 17 from ag to gg, which should interfere with catalytic step II of the pre-mRNA splicing reaction. In 1 MDS patient, a missense mutation was detected, which caused a replacement from Ser to Gly at codon 507 of p300. This is the first report of CBP/p300 mutations in leukemias, which might be relatively rare but nonetheless contribute to pathogenesis in some fraction of cases.

Acetyltransferases↗
PubMed2003

Reactive astrocytes express cAMP-response-element-binding protein (CREB) binding protein (CBP) in the central nervous system of transgenic mice expressing a human Cu/Zn superoxide dismutase mutation.

In the present study, we used the superoxide dismutase 1(SODI)(G93A) transgenic mice as an in vivo model of amyotrophic lateral sclerosis (ALS) and performed immunohistochemical studies to investigate the changes of cAMP-response-element-binding protein (CREB) binding protein (CBP) in the central nervous system of transgenic mice. The distribution of CBP-immunoreactive neurons was not different between control and transgenic mice, whereas CBP-immunoreactive astrocytes were found only in transgenic mice. CBP-immunoreactive astrocytes were detected in the spinal cord, brainstem, midbrain and cerebellar nuclei of transgenic mice. The present study provides the first evidence that CBP immunoreactive astrocytes were observed in the central nervous system of transgenic mice, suggesting that reactive astrocytes may play an important role in the pathogenesis and progress of ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2000

Extensive brain hemorrhage and embryonic lethality in a mouse null mutant of CREB-binding protein.

CREB-binding protein (CBP) is a transcriptional co-activator which is required by many transcription factors. Rubinstein-Taybi syndrome (RTS), which is an autosomal dominant syndrome characterized by abnormal pattern formation, is associated with mutations in the human CBP gene. Various abnormalities occur at high frequency in the skeletal system of heterozygous Cbp-deficient mice, but some features of RTS such as cardiac anomalies do not, suggesting that some symptoms of RTS are caused by a dominant-negative mechanism. Here we report the characterization of homozygous Cbp-deficient mice. Homozygous mutants died around E10.5-E12.5, apparently as a result of massive hemorrhage caused by defective blood vessel formation in the central nervous system, and exhibited apparent developmental retardation as well as delays in both primitive and definitive hematopoiesis. Cbp-deficient embryos exhibited defective neural tube closure which was similar to those observed in twist-deficient embryos. However, a decrease in the level of twist expression was not observed in Cbp-deficient embryos. Anomalous heart formation, a feature of RTS patients and mice mutated in the CBP-related molecule, p300, was not observed in Cbp-deficient embryos. Since both Cbp and p300 are ubiquitously expressed in embryonic tissues including the developing heart, these results suggest that cardiac anomalies observed in RTS patients may be caused by a dominant negative effect of mutant CBP.

Animals↗
PubMed2001

Contribution of steroid receptor coactivator-1 and CREB binding protein in ligand-independent activity of estrogen receptor beta.

Estrogens are essential regulators in the development and control of reproductive functions. The estrogenic signal is now known to be transduced by two estrogen receptors, ERalpha and ERbeta. Hormone-dependent transcriptional activation of ER and other nuclear receptors involves assembly of a coactivation complex which includes various cofactors such as the steroid receptor-coactivators (SRC) and CREB binding protein (CBP). Our findings on ERbeta have revealed a ligand-independent activation pathway which involves growth factor-mediated phosphorylation of ERbeta activation function-1 (AF-1) and subsequent recruitment of SRC-1 independently of the presence of estrogens. The presence of the cointegrator CBP is also shown to potentiate the SRC-1-mediated ERbeta ligand-independent activation, suggesting that CBP may participate in unliganded ERbeta coactivation. These findings demonstrate the ability of alternate signaling pathways to mediate coregulator assembly, hence resulting in ligand-independent activation of ERbeta.

CREB-Binding Protein↗
PubMedDate not supplied

Conditional modulation of glucocorticoid receptor activities by CREB-binding protein (CBP) and p300.

Coactivators of nuclear receptors are integral components of the signal transduction pathways of steroid hormones. Here, we show that one of the major coactivators of the glucocorticoid receptor (GR), CREB-binding protein (CBP), can also function conditionally as a negative regulator of its activities. Indeed, CBP suppressed the responsiveness of the mouse mammary tumor virus (MMTV) promoter to dexamethasone in a dose-dependent fashion in HeLa and A204 cells. Similarly, this protein suppressed the responsiveness of several glucocorticoid-responsive element (GRE)-containing synthetic promoters. Using deletion mutants of CBP, we localized the repressor effect of this protein to its N-terminal domain and showed that it was independent of the histone acetyltransferase and coactivator-binding domains but dependent upon its GR-binding domain. We also demonstrated functional differentiation between CBP and other coactivators, including SRC-1 and the CBP-related protein p300, both of which influenced GR signaling in a positive fashion. In fact, p300 completely antagonized the suppressive effects of CBP in a dose-dependent fashion, probably by competing with this protein at the level of the transcription complex. These findings suggest that CBP and p300 may function additively or antagonistically to each other depending on their relative concentrations and type of target tissue, to influence the sensitivity of tissues to glucocorticoids.

Animals↗
PubMed2001

CREB binding protein recruitment to the transcription complex requires growth factor-dependent phosphorylation of its GF box.

Growth factors such as epidermal growth factor (EGF) and insulin regulate development and metabolism via genes containing both POU homeodomain (Pit-1) and phorbol ester (AP-1) response elements. Although CREB binding protein (CBP) functions as a coactivator on these elements, the mechanism of transactivation was previously unclear. We now demonstrate that CBP is recruited to these elements only after it is phosphorylated at serine 436 by growth factor-dependent signaling pathways. In contrast, p300, a protein closely related to CBP that lacks this phosphorylation site, binds only weakly to the transcription complex and in a growth factor-independent manner. A small region of CBP (amino acids 312-440), which we term GF box, contains a potent transactivation domain and mediates this effect. Direct phosphorylation represents a novel mechanism controlling coactivator recruitment to the transcription complex.

Amino Acid Motifs↗
PubMed2006

Direct association between the CREB-binding protein (CBP) and nuclear receptor corepressor (N-CoR).

The binding of ligand to nuclear hormone receptors induces a conformational change that results in corepressor release and the recruitment of coactivator proteins that contain or recruit histone acetyltransferase (HAT) activity. As such, the coactivator and corepressor complexes and their associated HAT and histone deacytlase (HDAC) activities are often believed to be segregated into distinct complexes. However, there have been several reports that suggest that coactivators and corepressors may not be strictly segregated and in some cases even interact directly. In the present study, we have utilized a biochemical approach to assess whether the nuclear receptor corepressor (N-CoR) is capable of associating with the HAT coactivator CREB-binding protein (CBP). We demonstrate, using both immunoaffinity purification and conventional chromatography, that a subset of the N-CoR-HDAC3 complex copurifies with CBP in HeLa cells. In addition, indirect immunofluorescence also indicates an association between N-CoR and CBP in intact MCF-7 cells. This association may be direct as in vitro pulldown assays using recombinant purified proteins indicated that the amino terminus of N-CoR interacts directly with CBP. Interestingly, we also demonstrate that increasing concentrations of N-CoR are capable of attenuating CBP HAT activity in vitro, suggesting that N-CoR may have a functional role in modulating HAT activity. This is the first report of a direct interaction between N-CoR and CBP, and suggests that the role of N-CoR in mediating transcriptional events may be more complex than previously anticipated.

Blotting, Western↗