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PubMed2004

HOXB6 protein is bound to CREB-binding protein and represses globin expression in a DNA binding-dependent, PBX interaction-independent process.

Although HOXB6 and other HOX genes have previously been associated with hematopoiesis and leukemias, the precise mechanism of action of their protein products remains unclear. Here we use a biological model in which HOXB6 represses alpha- and gamma-globin mRNA levels to perform a structure/function analysis for this homeodomain protein. HOXB6 protein represses globin transcript levels in stably transfected K562 cells in a DNA-binding dependent fashion. However, the capacity to form cooperative DNA-binding complexes with the PBX co-factor protein is not required for HOXB6 biological activity. Neither the conserved extreme N-terminal region, a polyglutamic acid region at the protein C terminus, nor the Ser(214) CKII phosphorylation site was required for DNA binding or activity in this model. We have previously reported that HOX proteins can inhibit CREB-binding protein (CBP)-histone acetyltransferase-mediated potentiation of reporter gene transcription. We now show that endogenous CBP is co-precipitated with exogenous HOXB6 from nuclear and cytoplasmic compartments of transfected K562 cells. Furthermore, endogenous CBP co-precipitates with endogenous HOXB6 in day 14.5 murine fetal liver cells during active globin gene expression in this tissue. The CBP interaction motif was localized to the homeodomain but does not require the highly conserved helix 3. Our data suggest that the homeodomain contains most or all of the important structures required for HOXB6 activity in blood cells.

Acetyltransferases↗
PubMed2004

Stability of the hepatocyte nuclear factor 6 transcription factor requires acetylation by the CREB-binding protein coactivator.

We previously demonstrated that the formation of complexes between the DNA binding domains of the hepatocyte nuclear factor 6 (HNF6) and Forkhead Box a2 (Foxa2) transcription factors resulted in synergistic transcriptional activation of a Foxa2 target promoter. This Foxa2.HNF6 transcriptional synergy was mediated by the recruitment of CREB-binding protein (CBP) coactivator through the HNF6 Cut-Homeodomain sequences. Although the HNF6 DNA binding domain sequences are sufficient to recruit CBP coactivator for HNF6.Foxa2 transcriptional synergy, paradoxically these HNF6 Cut-Homeodomain sequences were unable to stimulate the transcription of an HNF6-dependent reporter gene. Here, we investigated whether the CBP coactivator protein played a different role in regulating HNF6 transcriptional activity. We showed that acetylation of the HNF6 protein by CBP increased both HNF6 protein stability and its ability to stimulate transcription of the glucose transporter 2 promoter. Mutation of the HNF6 Cut domain lysine 339 residue to an arginine residue abrogated CBP acetylation, which is required for HNF6 protein stability. Furthermore, the HNF6 K339R mutant protein, which failed to accumulate detected protein levels, was transcriptionally inactive and could not be stabilized by inhibiting the ubiquitin proteasome pathway. Finally, increased HNF6 protein levels stabilized the Foxa2 protein, presumably through the formation of the Foxa2.HNF6 complex. These studies show for the first time that HNF6 protein stability is controlled by CBP acetylation and provides a novel mechanism by which the activity of the CBP coactivator may regulate steady levels of two distinct liver-enriched transcription factors.

Animals↗
PubMed2004

Effects of depletion of CREB-binding protein on c-Myc regulation and cell cycle G1-S transition.

We recently reported that the transcriptional coactivator and histone acetyltransferase p300 plays an important role in the G(1) phase of the cell cycle by negatively regulating c-myc and thereby preventing premature G(1) exit (Kolli, et al. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 4646-4651; Baluchamy, et al. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 9524-9529). Because p300 does not substitute for all CREB-binding protein (CBP) functions, we investigated whether CBP also negatively regulates c-myc and prevents premature DNA synthesis. Here, we show that antisense-mediated depletion of CBP in serum-deprived human cells leads to induction of c-myc and that such cells emerge from quiescence without growth factors at a rate comparable with that of p300-depleted cells. The CBP-depleted cells contained significantly reduced levels of the cyclin-dependent kinase inhibitor p21 and low levels of p107 and p130 (but not pRb) phosphorylation, suggesting that these factors, along with elevated levels of c-Myc, contribute to induction of DNA synthesis. Antisense c-Myc reversed the phosphorylation of p107 and p130 and the induction of S phase in CBP-depleted cells, indicating that up-regulation of c-myc is directly responsible for the induction of S phase. Furthermore, the serum-stimulated p300/CBP-depleted cells did not traverse beyond S phase, and a significant number of these cells died of apoptosis, which was not related to p53 levels. These cells also contained significantly higher levels of c-Myc compared with normal cells. When c-myc expression was blocked by antisense c-Myc, the apoptosis of the serum-stimulated CBP-depleted cells was reversed, indicating that high levels of c-Myc contribute to apoptosis. Thus, despite their high degree of structural and functional similarities, normal levels of both p300 and CBP are essential for keeping c-myc in a repressed state in G(1) and thereby preventing inappropriate entry of cells into S phase. In addition, both these proteins also provide important functions in coordinated cell cycle progression.

CREB-Binding Protein↗
PubMed2004

Biochemical and NMR mapping of the interface between CREB-binding protein and ligand binding domains of nuclear receptor: beyond the LXXLL motif.

CBP, cAMP-response element-binding protein (CREB)-binding protein, plays an important role as a general cointegrator of various signaling pathways and interacts with a large number of transcription factors. Interactions of CBP with ligand binding domains (LBDs) of nuclear receptors are mediated by LXXLL motifs, as are those of p160 proteins, although the number, distribution, and precise sequences of the motifs differ. We used a large N-terminal fragment of murine CBP to map by biochemical methods and NMR spectroscopy the interaction domain of CBP with the LBDs of several nuclear receptors. We show that distinct zones of that fragment are involved in the interactions: a 20-residue segment containing the LXXLL motif (residues 61-80) is implicated in the interaction with all three domains tested (peroxisome proliferator-activated receptor gamma-LBD, retinoid X receptor alpha-LBD, and estrogen-related receptor gamma-LBD), whereas a second N-terminal well conserved block of around 25 residues centered on a consensus L(40)PDEL(44) motif constitutes a secondary motif of interaction with peroxisome proliferator-activated receptor gamma-LBD. Sequence analysis reveals that both zones are well conserved in all vertebrate p300/CBP proteins, suggesting their functional importance. Interactions of p300/CBP coactivators with the LBDs of nuclear receptors are not limited to the canonical LXXLL motifs, involving both a longer contiguous segment around the motif and, for certain domains, an additional zone.

Amino Acid Motifs↗
PubMed2004

Smad3 induces chondrogenesis through the activation of SOX9 via CREB-binding protein/p300 recruitment.

The transcriptional activation by SRY-type high mobility group box 9 (SOX9) and the transforming growth factor beta (TGF-beta) signals are necessary for chondrogenic differentiation. We have previously shown that CREB-binding protein (CBP/p300) act as an important SOX9 co-activator during chondrogenesis. In the present study, we investigated the relationship between TGF-beta-dependent Smad2/3 signaling pathways and the SOX9-CBP/p300 transcriptional complex at the early stage of chondrogenesis. Overexpressed Smad3 strongly induced the primary chondrogenesis of human mesenchymal stem cells. In addition, Smad3 enhanced the transcriptional activity of SOX9 and the expression of alpha1(II) collagen gene (COL2A1), and small interference RNA against Smad3 (si-Smad3) inhibited them. We observed that Smad2/3 associated with Sox9 in a TGF-beta-dependent manner and formed the transcriptional complexes with SOX9 on the enhancer region of COL2A1. Interestingly, the association between Sox9 and CBP/p300 was increased by Smad3 overexpression and was suppressed by si-Smad3. Our findings indicate that Smad3 has a stronger potential to stimulate the SOX9-dependent transcriptional activity by modulating the interaction between SOX9 and CBP/p300, rather than Smad2. This study suggests that the Smad3 pathway presents a key role for the SOX9-dependent transcriptional activation in primary chondrogenesis.

Adenoviridae↗
PubMed2005

Control of CREB-binding protein signaling by nuclear fibroblast growth factor receptor-1: a novel mechanism of gene regulation.

In integrative nuclear fibroblast growth factor receptor-1 (FGFR1) signaling a newly synthesized FGFR1 translocates to the nucleus to stimulate cell differentiation and associated gene activities. The present study shows that FGFR1 accumulates and interacts with the transcriptional co-activator CREB-binding protein (CBP) in nuclear speckle domains in the developing brain and in neural progenitor-like cells in vitro, which accompanies differentiation and postmitotic growth. Cell differentiation and gene activation by nuclear FGFR1 do not require tyrosine kinase activity. Instead, FGFR1 stimulates transcription in cooperation with CBP by increasing recruitment of RNA polymerase II and histone acetylation at the active gene promoter. FGFR1 is a multifactorial protein whose N terminus interacts with CBP and C terminus with ribosomal S6 kinase 1 (RSK1). Nuclear FGFR1 augments CBP-mediated transcription by 1) releasing the CBP C-terminal domain from RSK1 inhibition and 2) activating the CBP N-terminal domain. The interaction of FGFR1 with CBP and RSK1 allows activation of gene transcription and may play a role in cell differentiation.

Amino Acid Substitution↗
PubMed2006

The hormonal response of estrogen receptor beta is decreased by the phosphatidylinositol 3-kinase/Akt pathway via a phosphorylation-dependent release of CREB-binding protein.

The hormonal response of estrogen receptors (ER) alpha and ERbeta is controlled by a number of cofactors, including the general transcriptional coactivator CREB-binding protein (CBP). Growing evidence suggests that specific kinase signaling events also modulate the formation and activity of the ER coactivation complex. Here we show that ERbeta activity and target gene expression are decreased upon activation of ErbB2/ErbB3 receptors despite the presence of CBP. This inhibition of ERbeta involved activation of the phosphatidylinositol 3-kinase/Akt pathway, abrogating the potential of CBP to facilitate ERbeta response to estrogen. Such reduced activity was associated with an impaired ability of ERbeta to recruit CBP upon activation of Akt. Mutation of serine 255, an Akt consensus site contained in the hinge region of ERbeta, prevented the release of CBP and rendered ERbeta transcriptionally more responsive to CBP coactivation, suggesting that Ser-255 may serve as a regulatory site to restrain ERbeta activity in Akt-activated cells. In contrast, we found that CBP intrinsic activity was increased by Akt through threonine 1872, a consensus site for Akt in the cysteine- and histidine-rich 3 domain of CBP, indicating that such enhanced transcriptional potential of CBP did not serve to activate ERbeta. Interestingly, nuclear receptors sharing a conserved Akt consensus site with ERbeta also exhibit a reduced ability to be coactivated by CBP, whereas others missing that site were able to benefit from the activation of CBP by Akt. These results therefore outline a regulatory mechanism by which the phosphatidylinositol 3-kinase/Akt pathway may discriminate nuclear receptor response through coactivator transcriptional competence.

Animals↗
PubMed2007

The p38alpha/beta mitogen-activated protein kinases mediate recruitment of CREB-binding protein to preserve fast myosin heavy chain IId/x gene activity in myotubes.

In skeletal muscle, the transformation of fast into slow fiber type is accompanied by shifts in fiber type-specific gene expression that includes down-regulation of the adult fast fiber myosin heavy chain IId/x (MyHCIId/x) gene. Here, we report that the mitogen-activated protein kinases (MAPKs) p38alpha/beta regulate MyHCIId/x gene expression. Electrical stimulation of rabbit skeletal muscle cells with a slow fiber type activity pattern and treatment of C2C12 myotubes with Ca(2+)-ionophore inhibited p38alpha/beta MAPKs and reduced fast fiber type MyHC protein expression and promoter activity. Pharmacological inhibition of p38alpha/beta also down-regulated MyHCII gene expression. In controls, binding of the myocyte enhancer factor-2 (MEF-2) isoforms C and D as a heterodimer to a proximal consensus site within the MyHCIId/x promoter and recruitment of a transcriptional coactivator, the CREB-binding protein CBP, were observed. Overexpression of wild type MEF-2C but not of a MEF-2C mutant that cannot be phosphorylated by p38 induced promoter activity. Mutation of the MEF-2-binding site decreased the inducing effect of overexpressed CBP. Inhibition of p38alpha/beta MAPKs abolished CBP binding, whereas enforced induction of p38 by activated MAPK kinase 6 (MKK6EE) enhanced binding of CBP and increased promoter activity. Furthermore, knockdown of endogenous CBP by RNA interference eliminated promoter activation by MEF-2C or MKK6EE. In electrical stimulated and Ca(2+)-ionophore-treated myotubes, CBP was absent in complex formation at that site. Taken together, the data indicate that p38alpha/beta MAPKs-mediated coactivator recruitment at a proximal MEF-2 site is important for MyHCIId/x gene regulation in skeletal muscle.

Animals↗
PubMed2000

The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein.

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy, caused by mutations in the autoimmune regulator (AIRE) gene, is an autosomal recessive autoimmune disease characterized by the breakdown of tolerance to organ-specific antigens. The 545 amino acid protein encoded by AIRE contains several structural motifs suggestive of a transcriptional regulator and bears similarity to cellular proteins involved in transcriptional control. We show here that AIRE fused to a heterologous DNA binding domain activates transcription from a reporter promoter, and the activation seen requires the full-length protein or more than one activation domain. At the structural level AIRE forms homodimers through the NH(2)-terminal domain, and molecular modeling for this domain suggests a four-helix bundle structure. In agreement, we show that the common transcriptional coactivator CREB-binding protein (CBP) interacts with AIRE in vitro and in yeast nuclei through the CH1 and CH3 conserved domains. We suggest that the transcriptional transactivation properties of AIRE together with its interaction with CBP might be important in its function as disease-causing mutations almost totally abolish the activation effect.

Amino Acid Sequence↗
PubMed2003

Expression of cAMP response element binding protein (CREB)-binding protein (CBP) and the implication in retinoic acid-inducible transcription activation in human salivary gland adenocarcinoma cell line HSG.

In the process of retinoic acid (RA) signaling, retinoic acid receptor interacts with a coactivator complex composed of various transcription cofactors such as CREB-binding protein (CBP)/p300 and p160 family member proteins represented by steroid receptor coactivator-1 (SRC-1)/NCoA1 and p300/CBP cointegrator protein (p/CIP)/ACTR. In order to investigate the relationship of CBP to the RA signaling in a human salivary gland (HSG) adenocarcinoma cell line, we examined the expression of CBP in the cells. Immunoprecipitation and immunoblotting of the nuclear extract of HSG cells with anti-human CBP antibody showed a specific 270-kDa band, indicating the expression of CBP in HSG cells. The immunocytochemical analysis confirmed the nuclear localization of CBP. The transfection of HSG cells with a luciferase reporter plasmid harboring an RA-response element at the 5'-upstream region of the reporter gene increased RA-dependent luciferase activity approximately 3-fold. Co-transfection with a CBP-expression plasmid and the luciferase reporter gene enhanced the RA-dependent transcription activation approximately 10-fold. The immunoprecipitates obtained with anti-CBP antibody exhibited a histone acetyl-transferase (HAT) activity 2-fold higher than that obtained with the control antibody, whereas the HAT activity of the immunoprecipitates with anti-SRC-1 and anti-p/CIP, which were used as comparisons, were only a little increased. The RA treatment had no effect on the level of HAT activity except in the case of using the immunoprecipitate obtained with anti-RARalpha, in which case it increased the activity. These findings indicate that CBP expressed in HSG cells mediates the RA-inducible growth and differentiation-regulating transcription activation in concert with the retinoic acid receptors.

Acetyltransferases↗
PubMed2000

CREB-binding protein (CBP)/p300 and RNA polymerase II colocalize in transcriptionally active domains in the nucleus.

The spatial organization of transcription- associated proteins is an important control mechanism of eukaryotic gene expression. Here we analyzed the nuclear distribution of the transcriptional coactivators CREB-binding protein (CBP)/p300 in situ by confocal laser scanning microscopy, and in vivo complex formation by coimmunoprecipitation. A subpopulation of CBP and p300 is targeted to active sites of transcription and partially colocalizes with hyper- and hypophosphorylated RNA polymerase II (pol II) in discrete regions of variable size throughout the nucleus. However, the coactivators were found in tight association with hypophosphorylated, but not hyperphosphorylated pol II. Transcriptional inhibition induced a relocation of CBP/p300 and pol II into speckles. Moreover, double and triple immunofluorescence analyses revealed the presence of CBP, p300, and pol II in a subset of promyelocytic leukemia (PML) bodies. Our results provide evidence for a dynamic spacial link between coactivators of transcription and the basal transcription machinery in discrete nuclear domains dependent upon the transcriptional activity of the cell. The identification of pol II in CBP/PML-containing nuclear bodies supports the idea that transcription takes place at PML bodies.

Acetyltransferases↗
PubMed2002

Prothymosin alpha interacts with the CREB-binding protein and potentiates transcription.

Prothymosin alpha (ProTalpha) is a histone H1-binding protein localized in sites of active transcription in the nucleus. We report here that ProTalpha physically interacts with the CREB-binding protein (CBP), which is a versatile transcription co-activator. Confocal laser scanning microscopy reveals that ProTalpha partially colocalizes with CBP in discrete subnuclear domains. Using transient transfections, we show that ProTalpha synergizes with CBP and stimulates AP1- and NF-kappaB-dependent transcription. Furthermore, overexpression of ProTalpha enhances the transactivation potential of CBP. These findings reveal a new function for ProTalpha in transcription activation, probably through CBP-mediated recruitment to different promoters.

Animals↗
PubMed2000

CREB-binding protein sequestration by expanded polyglutamine.

Spinal and bulbar muscular atrophy (SBMA) is one of eight inherited neurodegenerative diseases known to be caused by CAG repeat expansion. The expansion results in an expanded polyglutamine tract, which likely confers a novel, toxic function to the affected protein. Cell culture and transgenic mouse studies have implicated the nucleus as a site for pathogenesis, suggesting that a critical nuclear factor or process is disrupted by the polyglutamine expansion. In this report we present evidence that CREB-binding protein (CBP), a transcriptional co-activator that orchestrates nuclear response to a variety of cell signaling cascades, is incorporated into nuclear inclusions formed by polyglutamine-containing proteins in cultured cells, transgenic mice and tissue from patients with SBMA. We also show CBP incorporation into nuclear inclusions formed in a cell culture model of another polyglutamine disease, spinocerebellar ataxia type 3. We present evidence that soluble levels of CBP are reduced in cells expressing expanded polyglutamine despite increased levels of CBP mRNA. Finally, we demonstrate that over-expression of CBP rescues cells from polyglutamine-mediated toxicity in neuronal cell culture. These data support a CBP-sequestration model of polyglutamine expansion disease.

Animals↗
PubMed2002

Requirements for utilization of CREB binding protein by hypersensitive site two of the beta-globin locus control region.

Strong transactivation of the beta-globin genes is conferred by the beta-globin locus control region (LCR), which consists of four erythroid-specific DNase I hypersensitive sites (HS1-HS4). HS2 has a powerful enhancer activity dependent upon tandem binding sites for the erythroid cell- and megakaryocyte-specific transcription factor NF-E2. An important co-activator-mediating transactivation by HS2 is the histone acetyltransferase (HAT) CREB binding protein (CBP). We showed previously that recruitment of a GAL4-CBP fusion protein to HS2 largely bypassed the requirement of the NF-E2 sites for transactivation. To determine whether GAL4-CBP recruitment is sufficient for transactivation, we assessed the importance of cis-elements within HS2. Docking of GAL4-CBP upstream of an Agamma-globin promoter lacking HS2 only weakly activated the promoter, indicating that HS2 components are required for GAL4-CBP-mediated transactivation. Sequences upstream and downstream of the NF-E2 sites were required for maximal GAL4-CBP-mediated transactivation, and HAT catalytic activity of GAL4-CBP was critical. No single factor-binding site was required for GAL4-CBP-mediated transactivation. However, deletion of two sites, a CACC site and an E-box, abolished transactivation in transient and stable transfection assays. These results suggest that NF-E2 recruits CBP as a critical step in transactivation, but additional components of HS2 are required to achieve maximal enhancer activity.

Acetyltransferases↗
PubMed1997

The adenovirus 12 E1A proteins can bind directly to proteins of the p300 transcription co-activator family, including the CREB-binding protein CBP and p300.

The cellular transcription co-activators p300 and the CREB-binding protein CBP are cellular targets for transformation by the E1A proteins of non-oncogenic adenovirus 5 (Ad5). In this study, we show that the E1A proteins of oncogenic Ad12, like those of Ad5, can also bind to CBP and that this interaction is direct. In addition, we show that the Ad12 E1A proteins can also bind directly to p300. These results suggest that E1A can modulate the function of proteins of the p300 family via direct protein-protein interactions.

Adenoviridae↗
PubMed1996

SREBP transcriptional activity is mediated through an interaction with the CREB-binding protein.

The sterol regulatory element binding proteins (SREBP-1 and -2) activate transcription of genes whose products are involved in the cellular uptake and synthesis of cholesterol. Although considerable effort has been exerted to define the events regulating the levels of active SREBP, little is known about the transcriptional cofactors mediating SREBP function. In an unbiased search for potential coactivators of SREBP, we isolated a protein of 265 kD from HeLa cells that directly bound SREBP-1 and SREBP-2. Peptide sequencing and Western blot analysis established that the 265-kD protein was CBP (CREB-binding protein), a recently identified transcriptional coactivator. The putative activation domain of SREBP was shown to bind specifically to amino-terminal domains of recombinant CBP and p300 (a CBP-related protein). Moreover, transfection studies demonstrated that CBP enhances the ability of SREBP to activate transcription of reporter genes in HeLa cells. Together, these data suggest that CBP mediates SREBP transcriptional activity, thus revealing a new step in the biochemical pathway regulating cholesterol metabolism.

Animals↗
PubMed2003

Aberrant histone acetylation, altered transcription, and retinal degeneration in a Drosophila model of polyglutamine disease are rescued by CREB-binding protein.

Sequestration of the transcriptional coactivator CREB-binding protein (CBP), a histone acetyltransferase, has been implicated in the pathogenesis of polyglutamine expansion neurodegenerative disease. We used a Drosophila model to demonstrate that polyglutamine-induced neurodegeneration is accompanied by a defect in histone acetylation and a substantial alteration in the transcription profile. Furthermore, we demonstrate complete functional and morphological rescue by up-regulation of endogenous Drosophila CBP (dCBP). Rescue of the degenerative phenotype is associated with eradication of polyglutamine aggregates, recovery of histone acetylation, and normalization of the transcription profile. These findings suggest that histone acetylation is an early target of polyglutamine toxicity and indicate that transcriptional dysregulation is an important part of the pathogenesis of polyglutamine-induced neurodegeneration.

Acetylation↗
PubMedDate not supplied

Transgenic mice expressing a truncated form of CREB-binding protein (CBP) exhibit deficits in hippocampal synaptic plasticity and memory storage.

Deletions, translocations, or point mutations in the CREB-binding protein (CBP) gene have been associated with Rubinstein-Taybi Syndrome; a human developmental disorder characterized by retarded growth and reduced mental function. To examine the role of CBP in memory, transgenic mice were generated in which the CaMKII alpha promoter drives expression of an inhibitory truncated CBP protein in forebrain neurons. Examination of hippocampal long-term potentiation (LTP), a form of synaptic plasticity thought to underlie memory storage, revealed significantly reduced late-phase LTP induced by dopamine-regulated potentiation in hippocampal slices from CBP transgenic mice. However, four-train induced late-phase LTP is normal. Behaviorally, CBP transgenic mice exhibited memory deficits in spatial learning in the Morris water maze and deficits in long-term memory for contextual fear conditioning, two hippocampus-dependent tasks. Together, these results demonstrate that CBP is involved in specific forms of hippocampal synaptic plasticity and hippocampus-dependent long-term memory formation.

Animals↗