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Results for “CREB-Binding Protein”

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At least 19 recordsLinked to original sources
PubMed1993

Identification of proteins that interact with CREB during differentiation of F9 embryonal carcinoma cells.

The mammalian transcription factor CREB is thought to activate cAMP-inducible genes in a variety of differentiated cell types and is probably involved in other signalling pathways. Undifferentiated F9 embryonal carcinoma (UF9) cells are refractory to cAMP and become cAMP-responsive following differentiation to endoderm like cells. It has been proposed that UF9 cells contain a negative regulator(s) of the cAMP-response that might act through direct interaction with CREB. We have used a protein blotting assay and 32P-labelled CREB to probe for CREB-binding proteins in nuclear extracts from F9 cells and to examine their abundance during differentiation. We find that ATF1 (a protein that is highly homologous to CREB) and a novel polypeptide(s) of approximately 100 kDa (CBP100) are the major CREB-binding proteins in extracts from UF9 cells. As expected ATF1 is detected due to leucine zipper-dependent heterodimerisation with CREB. In contrast CBP100 interacts with CREB independently of the leucine zipper. The total amount of ATF1 and the amount of ATF1 that is complexed with CREB are substantially reduced following differentiation. In addition, ATF1 mRNA levels are lower in differentiated F9 cells indicating that a pretranslational mechanism contributes to the decreased ATF1 protein levels observed. CBP100 levels are also reduced or CBP100 is modified upon differentiation. We discuss the potential roles of ATF1 and CBP100 in regulating CREB activity during differentiation of F9 embryonal carcinoma cells.

Amino Acid Sequence↗
PubMed2025

Histone Arginine Methylation Regulates Neuropeptide Y Expression in the Basolateral Amygdala to Promote Reward-Seeking Behaviour.

The basolateral amygdala (BLA) serves in the evaluation of reward. However, the causal molecular substrates in the BLA necessary for reward seeking behaviour are largely unknown. Reward conditioning induces long-lasting changes in epienzymes in limbic areas, including the amygdala. The current study probed the role of histone arginine methylation as a novel epigenetic mechanism in neuropeptide Y (NPY) gene regulation in the BLA during reward and reinforcement. For reward conditioning, adult Wistar rats were trained to self-administer sucrose pellets in a nose-poke operant chamber. Reward conditioning increased protein arginine methyltransferase 4 (PRMT4) and NPY in the BLA. Moreover, after operant conditioning, histone arginine methylation (H3R17me2a) and PRMT4 occupancy at the NPY promoter were heightened. PRMT4 was predominantly colocalised in the nucleus of the NPY-expressing cells in the BLA. Intra-BLA administration of specific siRNA or inhibitor of PRMT4 after conditioning waned the nose-poke activity, which was further reinstated during the subsequent 5 days. These effects of PRMT4 repression were correlated with the NPY expression and H3R17me2a levels at the NPY promoter. Furthermore, NPY peptide administration after PRMT4 siRNA or inhibitor infusion in BLA restored the nose-poke activity. PRMT4 is known to interact with CREB-binding protein (CBP). Therefore, co-occupancy of PRMT4 and CBP resulted in heightened histone acetylation (H3K14ac) in the conditioned rats. The current study suggests a pivotal role of PRMT4-mediated histone arginine methylation in NPY gene expression in the amygdala necessary for the reward-seeking behaviour.

Animals↗
PubMed1995

A family of transcriptional adaptor proteins targeted by the E1A oncoprotein.

The cellular protein p300 is a target of the adenoviral E1A oncoprotein and is thought to participate in preventing the G0/G1 transition in the cell cycle, activating certain enhancers and stimulating differentiation pathways. CBP is a protein that is associated with and coactivates the transcription factor CREB, mediating the induction by cyclic AMP of certain responsive promoters. The sequences of p300 and CBP are highly related. We show here that p300, like CBP2, can stimulate transcription. This activity is directly and specifically inhibited by E1A. We also find that CBP exists in a DNA-bound complex containing a member of the CREB family and that E1A and CBP interact with one another in vivo. In keeping with the idea that E1A functionally targets CBP, cAMP-dependent transcription is repressed by E1A. Thus, p300 and CBP define a family of transcriptional adaptor proteins that are specifically targeted by the E1A oncoprotein.

Adenovirus E1A Proteins↗
PubMed2026

The CTNNB1-TRIM28 complex governs hormone-induced RNA polymerase II dynamics in kidney epithelial cells.

Arginine vasopressin maintains water homeostasis by regulating epithelial water permeability through complex transcriptional mechanisms in kidney collecting duct cells. Although CTNNB1 (β-catenin) functions as a transcriptional coregulator in vasopressin-responsive gene transcription, its role remains poorly understood. To identify CTNNB1-dependent components mediating the vasopressin-responsive transcription, we profiled transcriptomic changes following Ctnnb1 knockdown in mouse kidney collecting duct cells using RNA sequencing (RNA-Seq). RNA-Seq and promoter enrichment analyses identified bromodomain-containing proteins (TRIM28, TRIM33, BRD4, CREBBP, and EP300) as components of a CTNNB1-dependent complex regulating RNA Polymerase II (Pol II) activity. Biochemical analyses revealed physical interactions between TRIM28, CTNNB1, Pol II, and CDK9. Functionally, Trim28 knockdown blunted vasopressin-induced expression of the Aqp2 gene. Quantitative genomic binding assays demonstrated that TRIM28 is required for robust genomic occupancy and stabilization of Pol II at the transcription start site of Aqp2. Additionally, dynamic formation of phase-separated nuclear TRIM28 condensates in response to vasopressin suggests that TRIM28-associated machinery functions at specialized chromatin hubs. These findings reveal that TRIM28 facilitates Pol II recruitment, pause release, and elongation upon vasopressin stimulation. Our study establishes the CTNNB1-TRIM28 machinery as a critical transcriptional scaffold that controls Pol II dynamics and chromatin structure, thereby driving osmotic water reabsorption and urine concentration.

Animals↗
PubMed1995

CBP-induced stimulation of c-Fos activity is abrogated by E1A.

The CBP protein stimulates transcription of cAMP-responsive genes by binding to the phosphorylated activation domain of the CREB transcription factor. Here we show that CBP stimulates transcription of Fos/Jun activity in F9 cells and that this response of mediated, at least partly, via c-Fos. We show that CBP binds c-Fos in a phosphorylation-independent manner in vitro, using a domain distinct from that required to bind CREB. When this CBP domain is linked to the activation domain of VP16 it can stimulate GAL4-Fos activity in vivo. The domain of CBP that binds c-Fos is also used to contact the E1A protein. We therefore asked whether the documented repression of AP1 activity by E1A is due to sequestration of CBP from c-Fos. We show that E1A 12S can repress c-Fos activation functions. The use of E1A mutants indicates that binding of CBP, but not RB, to E1A is essential for E1A-mediated repression. These data support a model whereby E1A can modulate AP1 activity by directly competing for the CBP co-activator protein.

Adenovirus E1A Proteins↗
PubMed1995

Adenoviral E1A-associated protein p300 as a functional homologue of the transcriptional co-activator CBP.

The 265K nuclear protein CBP was initially identified as a co-activator for the protein kinase A (PKA)-phosphorylated form of the transcription factor CREB. The domains in CBP that are involved in CREB binding and transcriptional activation are highly related to the adenoviral E1A-associated cellular protein p300 (refs 2, 3), and to two hypothetical proteins from Caenorhabditis elegans, R10E11.1 and K03H1.10 (refs 4 and 5, respectively), whose functions are unknown. Here, we show that CBP and p300 have similar binding affinity for the PKA-phosphorylated form of CREB, and that p300 can substitute for CBP in potentiating CREB-activated gene expression. We find that E1A binds to CBP through a domain conserved with p300 and represses the CREB-dependent co-activator functions of both CBP and p300. Our results indicate that the gene repression and cell immortalization functions associated with E1A involve the inactivation of a family of related proteins that normally participate in second-messenger-regulated gene expression.

Adenovirus E1A Proteins↗
PubMed2026

A bivalent molecular glue linking lysine acetyltransferases to oncogene-induced cell death.

Developing cancer therapies that induce specific death of malignant cells is critical for preventing relapse. Highly effective strategies, such as immunotherapy, exemplify this principle. Here, we provide the mechanistic basis for a small-molecule approach that leverages chemically induced proximity (CIP) to kill diffuse large B cell lymphoma, the most common non-Hodgkin lymphoma. We developed lysine acetyltransferase (KAT)-based TCIPs (transcriptional/epigenetic chemical inducers of proximity), or KAT-TCIPs, which redirect p300/CREB-binding protein (CBP) to activate cell-death networks repressed by the oncogenic driver BCL6. Our lead KAT-TCIP reprograms the epigenome to initiate apoptosis. The crystal structure of the chemically induced p300-BCL6 complex reveals how chance protein-protein interactions may be exploited to confer the potency and selectivity of KAT-TCIPs. Thus, oncogenic drivers can be co-opted to activate robust cell death. Consistent with their gain-of-function mechanism, TCIPs recruiting different transcriptional activators-p300, BRD4, or CDK9-produce distinct genomic responses, suggesting specialized therapeutic uses.

Humans↗
PubMed1995

Multiple protein kinase A-regulated events are required for transcriptional induction by cAMP.

The second messenger cAMP stimulates the expression of numerous genes via the protein kinase A-mediated phosphorylation of the cAMP response element-binding protein (CREB) at Ser-133. Ser-133 phosphorylation, in turn, appears to induce target gene expression by promoting interaction between CREB and CBP, a 265-kDa nuclear phospho-CREB-binding protein. It is unclear, however, whether Ser-133 phosphorylation per se is sufficient for CREB-CBP complex formation and for target gene induction in vivo. Here we examine CREB activity in Jurkat T cells after stimulation of the T-cell receptor (TCR), an event that leads to calcium entry and diacylglycerol production. Triggering of the TCR stimulated Ser-133 phosphorylation of CREB with high stoichiometry, but TCR activation did not promote CREB-CBP complex formation or target gene induction unless suboptimal doses of cAMP agonist were provided as a costimulus. Our results demonstrate that, in addition to mediating Ser-133 phosphorylation of CREB, protein kinase A regulates additional proteins that are required for recruitment of the transcriptional apparatus to cAMP-responsive genes.

CREB-Binding Protein↗
PubMed1995

Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP.

The Rubinstein-Taybi syndrome (RTS) is a well-defined syndrome with facial abnormalities, broad thumbs, broad big toes and mental retardation as the main clinical features. Many patients with RTS have been shown to have breakpoints in, and microdeletions of, chromosome 16p13.3 (refs 4-8). Here we report that all these breakpoints are restricted to a region that contains the gene for the human CREB binding protein (CBP), a nuclear protein participating as a co-activator in cyclic-AMP-regulated gene expression. We show that RTS results not only from gross chromosomal rearrangements of chromosome 16p, but also from point mutations in the CBP gene itself. Because the patients are heterozygous for the mutations, we propose that the loss of one functional copy of the CBP gene underlies the developmental abnormalities in RTS and possibly the propensity for malignancy.

Amino Acid Sequence↗
PubMed1994

Nuclear protein CBP is a coactivator for the transcription factor CREB.

The transcription factor CREB binds to a DNA element known as the cAMP-regulated enhancer (CRE). CREB is activated through phosphorylation by protein kinase A (PKA), but precisely how phosphorylation stimulates CREB function is unknown. One model is that phosphorylation may allow the recruitment of coactivators which then interact with basal transcription factors. We have previously identified a nuclear protein of M(r)265K, CBP, that binds specifically to the PKA-phosphorylated form of CREB. We have used fluorescence anisotropy measurements to define the equilibrium binding parameters of the phosphoCREB:CBP interaction and report here that CBP can activate transcription through a region in its carboxy terminus. The activation domain of CBP interacts with the basal transcription factor TFIIB through a domain that is conserved in the yeast coactivator ADA-1 (ref. 8). Consistent with its role as a coactivator, CBP augments the activity of phosphorylated CREB to activate transcription of cAMP-responsive genes.

Animals↗
PubMed1994

Activation of cAMP and mitogen responsive genes relies on a common nuclear factor.

A number of signalling pathways stimulate transcription of target genes through nuclear factors whose activities are primarily regulated by phosphorylation. Cyclic AMP regulates the expression of numerous genes, for example, through the protein kinase-A (PKA)-mediated phosphorylation of transcription factor CREB at Ser 133. Although phosphorylation may stimulate transcriptional activators by modulating their nuclear transport or DNA-binding affinity, CREB belongs to a class of proteins whose phosphorylation appears specifically to enhance their trans-activation potential. Recent work describing a phospho-CREB binding protein (CBP) which interacts specifically with the CREB trans-activation domain prompted us to examine whether CBP is necessary for cAMP regulated transcription. We report here that microinjection of an anti-CBP antiserum into fibroblasts can inhibit transcription from a cAMP responsive promoter. Surprisingly, CBP also cooperates with upstream activators such as c-Jun, which are involved in mitogen responsive transcription. We propose that CBP is recruited to the promoter through interaction with certain phosphorylated factors, and that CBP may thus play a critical role in the transmission of inductive signals from cell surface receptor to the transcriptional apparatus.

3T3 Cells↗
PubMed1995

An inactivating point mutation demonstrates that interaction of cAMP response element binding protein (CREB) with the CREB binding protein is not sufficient for transcriptional activation.

The cAMP response element binding protein (CREB) mediates transcriptional activation in response to the cAMP signaling pathway. Several recent studies have suggested that phosphorylation-dependent interaction of CREB with a co-activator designated CREB binding protein (CBP) is a crucial step in mediating transcriptional responses to cAMP. In the present study we have determined that replacement of Ser142 of CREB with Asp greatly decreases the ability of the cAMP-dependent protein kinase to activate CREB. As Ser142 is located within the region of CREB that interacts with CBP, it seemed quite likely that mutations at this site might interfere with binding to CBP. However, both in vitro and in vivo protein-protein interaction assays revealed that replacement of Ser142 with Asp does not interfere with the binding of CREB to CBP. These studies argue strongly that although the binding of CREB to CBP is necessary, it is not sufficient for transcriptional responses to cAMP.

Animals↗
PubMed1995

A C4HC3 zinc finger motif.

Metal-binding cysteine and histidine residues are often used to stabilise a protein fold through coordination of zinc ions. These zinc fingers are either involved in nucleic acid binding (TFIIIA, GAL4, nuclear receptors, retroviral gag...) or in yet unidentified biochemical functions (LIM and RING domains). The latter characterized by a unique histidine residue in the zinc binding motif (C2HC5 and C3HC4 for the LIM and RING respectively) may constitute protein/protein interaction interfaces. We have identified a new C4HC3 motif in a variety of proteins including the Drosophila trithorax and its human homologue ALL-1 involved in oncogenic translocations in acute leukaemias. This domain, for which we propose the name TTC (for trithorax consensus) is found in many transcriptional regulators or DNA-binding proteins. Interestingly, TTC was found in several bromodomain containing transcriptional adaptors including the E1A-binding p300 and the CREB-binding CBP proteins. In CBP, this domain does not appear to be involved in DNA, CREB or TFIIB binding. In the chromosomal translocations that involve the 11q23 locus, the C-terminal end of ALL-1 (which contains 4 TTC fingers) is constantly lost. The absence of these motifs in the fusion genes may relate to their leukemogenic potential.

Amino Acid Sequence↗
PubMed1995

cAMP response element-binding protein (CREB) interacts with transcription factors IIB and IID.

cAMP response element-binding protein (CREB) participates in both constitutive and cAMP-induced transcription of cAMP-responsive genes. CREB-mediated constitutive transcription requires only CREB-binding sites and a minimal promoter region (containing the TATA through start sequences), indicating that CREB interacts directly with components of the general transcription machinery. In this study, a coimmunoprecipitation assay was used to test for interaction of CREB with the general transcription factors (TF) TFIIB and TFIID and the core component of TFIID, TATA-binding protein (TBP). Human TFIIB and TBP, tagged with distinct epitopes (eTFIIB and eTBP), were expressed in and purified from Escherichia coli, and holo-eTFIID, containing eTBP, was obtained from the HeLa cell line LTR alpha 3. 35S-Labeled CREB, synthesized in vitro and incubated with eTFIIB, was coimmunoprecipitated with antibody recognizing eTFIIB, indicating that CREB specifically binds to TFIIB. 35S-CREB was coimmunoprecipitated with antibody against eTBP, but only when incubated with the holo-eTFIID complex, not with eTBP alone. TFIIB interacted with TBP, but CREB was not coprecipitated with the eTBP antibody when incubated with eTBP plus TFIIB, so CREB did not form a stable ternary complex with TFIIB and TBP. Conversely, depletion of TFIIB from the holo-TFIID preparation did not diminish the level of interaction between CREB and TFIID. Thus, CREB interacts independently with TFIIB and TFIID, but not directly with TBP. A protein kinase A phosphorylation site mutant of CREB and wild-type CREB exhibited equivalent interaction with TFIIB, indicating that this phosphorylation is not required. Consistent with the role of CREB in promoting constitutive or basal transcription, the constitutive activation domain of CREB was sufficient for interaction with both TFIIB and TFIID.

Cyclic AMP Response Element-Binding Protein↗