Intrinsic Histone Acetyltransferase Activity Research Articles

1α,25‐dihydroxy vitamin D3‐enhanced expression of the osteocalcin gene involves increased promoter occupancy of basal transcription regulators and gradual recruitment of the 1α,25‐dihydroxy vitamin D3 receptor‐SRC‐1 coactivator complex

Binding of 1alpha,25-dihydroxy vitamin D(3) to the C-terminal ligand-binding domain (LBD) of its receptor (VDR) induces a conformational change that enables interaction of VDR with transcriptional coactivators such as members of the p160/SRC family or the DRIP (vitamin D receptor-interacting complex)/Mediator complex. These interactions are critical for VDR-mediated transcriptional enhancement of target genes. The p160/SRC members contain intrinsic histone acetyl transferase (HAT) activities that remodel chromatin at promoter regulatory regions, and the DRIP/Mediator complex may establish a molecular bridge between the VDR complex and the basal transcription machinery. Here, we have analyzed the rate of recruitment of these coactivators to the bone-specific osteocalcin (OC) gene in response to short and long exposures to 1alpha,25-dihydroxy vitamin D3. We report that in intact osteoblastic cells VDR, in association with SRC-1, rapidly binds to the OC promoter in response to the ligand. The recruitment of SRC-1 correlates with maximal transcriptional enhancement of the OC gene at 4 h and with increased histone acetylation at the OC promoter. In contrast to other 1alpha,25-dihydroxy vitamin D3-enhanced genes, binding of the DRIP205 subunit, which anchors the DRIP/Mediator complex to the VDR, is detected at the OC promoter only after several hours of incubation with 1alpha,25-dihydroxy vitamin D(3), concomitant with the release of SRC-1. Together, our results support a model where VDR preferentially recruits SRC-1 to enhance bone-specific OC gene transcription.

Transgenic mice expressing an inhibitory truncated form of p300 exhibit long-term memory deficits

The formation of many forms of long-term memory requires several molecular mechanisms including regulation of gene expression. The mechanisms directing transcription require not only activation of individual transcription factors but also recruitment of transcriptional coactivators. CBP and p300 are transcriptional coactivators that interact with a large number of transcription factors and regulate transcription through multiple mechanisms, including an intrinsic histone acetyltransferase (HAT) activity. HAT activity mediates acetylation of lysine residues on the amino-terminal tails of histone proteins, thereby increasing DNA accessibility for transcription factors to activate gene expression. CBP has been shown to play an important role in long-term memory formation. We have investigated whether p300 is also required for certain forms of memory. p300 shares a high degree of homology with CBP and has been shown to interact with transcription factors known to be critical for long-term memory formation. Here we demonstrate that conditional transgenic mice expressing an inhibitory truncated form of p300 (p300Delta1), which lacks the carboxy-terminal HAT and activation domains, have impaired long-term recognition memory and contextual fear memory. Thus, our study demonstrates that p300 is required for certain forms of memory and that the HAT and carboxy-terminal domains play a critical role.

MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells

Genes of the human monocytic leukemia zinc-finger protein MOZ (HUGO symbol, MYST3) and its paralog MORF (MYST4) are rearranged in chromosome translocations associated with acute myeloid leukemia and/or benign uterine leiomyomata. Both proteins have intrinsic histone acetyltransferase activity and are components of quartet complexes with noncatalytic subunits containing the bromodomain, plant homeodomain-linked (PHD) finger and proline-tryptophan-tryptophan-proline (PWWP)-containing domain, three types of structural modules characteristic of chromatin regulators. Although leukemia-derived fusion proteins such as MOZ-TIF2 promote self-renewal of leukemic stem cells, recent studies indicate that murine MOZ and MORF are important for proper development of hematopoietic and neurogenic progenitors, respectively, thereby highlighting the importance of epigenetic integrity in safeguarding stem cell identity.

Polyamine‐mediated regulation of protein acetylation in murine skin and tumors

Overexpression of ornithine decarboxylase (ODC), resulting in increased polyamine metabolism, is a common feature of epithelial tumors. Polyamines play a complex role in promoting tumor development, affecting diverse cellular processes, including gene expression. One way polyamines may affect gene expression is to modulate the multiprotein complexes comprised of transcription factors and coregulatory factors that alter chromatin structure by acetylating/deacetylating nearby histones. We have capitalized on ODC-overexpressing cultured cells and K6/ODC and ODC/Ras transgenic mouse models, in which ODC overexpression is targeted to hair follicles, to evaluate the influence of polyamines on the acetylation of histones and other proteins. ODC overexpression was found to alter intrinsic histone acetyltransferase (HAT) and deacetylase activities and histone acetylation patterns. The high HAT activity exhibited by ODC transgenic mouse skin and tumors might be partly attributed to enhanced p300/creb-binding protein (CBP)-associated HAT activity and increased levels of Tat interactive protein, 60 kDa (Tip60) HAT protein isoforms. Altered association of Tip60 with E2F1 and a subset of newly identified Tip60-interacting transcription factors was detected in ODC mouse skin and tumors, implying novel polyamine modulation of Tip60-regulated gene expression. Polyamine effects on HAT enzymes also influence the acetylation status of nonhistone proteins. Overexpression of ODC in skin serves as a novel stimulus for acetylation of the tumor suppressor protein, p53--a target of both p300/CBP and Tip60--with concomitant increased binding to, and increased transcription of, a downstream target gene. The future challenge will be to elucidate the multiple mechanisms by which polyamines influence enzymes that regulate protein acetylation and gene transcription to promote cancer.

Stability of Nmi protein is controlled by its association with Tip60

Tip60 exerts diverse biological functions through mechanisms that are either dependent or independent on its intrinsic histone acetyltransferase activity. In the present study, we identified Nmi (N-Myc and STATs Interactor) as a novel binding partner for Tip60 by a yeast two-hybrid screen. The association of Tip60 with Nmi was further confirmed by coimmunoprecipitation in mammalian cells. The zinc finger domain of Tip60 interacts with the NID repeats of Nmi, a region essential for the cytoplamic localization and homo- and heterodimerization of Nmi. We further showed that Nmi is an unstable protein and is targeted for proteasome-mediated degradation. The stability of Nmi can be enhanced by its association with Tip60, a process that is dependent on histone acetyltransferase activity of Tip60. The stabilization of Nmi by Tip60 is in part mediated by the translocation of Tip60 into cytoplasm to form distinct large cytoplasmic speckles. Our finding that Tip60 stabilizes Nmi through the formation of distinct cytoplasmic speckles provides a new mechanism to modulate Nmi-mediated functions.

Histone acetyltransferase p300 acts as a potent transcriptional co-activator for Pax5 (35.29)

Abstract Pax5/BSAP is an essential regulator for B lineage cell development and function. Pax5 activates the transcription of many B lineage specific genes, such as Cd19, Mb-1 and Blnk; controls the B lineage specific IgH VH→DJH recombination and meantime, represses the expression of other lineage inappropriate genes, such as Notch1, M-csfr, G-csfr, and Ccl3, to restrict B lineage cell development. It becomes important to understand how the Pax5 activity is regulated to exert these different functions. Here, we show that co-expression of histone acetyltransferase p300 dramatically enhances Pax5-mediated activation of a Pax5 responsive luciferase reporter construct. The p300-mediated enhancement is dependent on the intrinsic histone acetyltransferase activity of p300 and the activation domain of Pax5. Pax5 interacts with p300 in vitro and forms a complex with p300 in B lineage cells. Recombinant full length p300 purified from baculovirus or 293 cells directly acetylates purified Pax5 in vitro and overexpression of p300 induces Pax5 acetylation in 293 cells. Mass spectroscopy-based analysis identified that multiple lysine residues within the Pax5 DNA binding domain were acetylated upon coexpression of p300. Mutations of lysine 67, 87, 89, 103, and 142 residues on Pax5 attenuate p300-mediated enhancement. These results suggest that p300 acts as a potent co-activator for Pax5-mediated transcription function through acetylation of the Pax5 DNA binding domain.

Histone Deacetylase Inhibitors Synergize p300 Autoacetylation that Regulates Its Transactivation Activity and Complex Formation

p300/cyclic AMP-responsive element binding protein-binding protein (CBP) are general coactivators for multiple transcription factors involved in various cellular processes. Several highly conserved domains of p300/CBP serve as interacting sites for transcription factors and regulatory proteins. Particularly, the intrinsic histone acetyltransferase (HAT) activity and transactivation domains (TAD) play essential roles for their coactivating function. Autoacetylation of p300/CBP is commonly observed in cell-free HAT assays and has been implicated in the regulation of their HAT activity. Here, we show that six lysine-rich regions in several highly conserved functional domains of p300 are targeted by p300HAT for acetylation in cell-free systems. We show that p300 is susceptible to acetylation in cultured tumor cells and that its acetylation status is affected by histone deacetylase inhibitor trichostatin A. We further show that either treatment with deacetylase inhibitors or coexpression of Gal4-p300HAT, which alone has no transactivation activity, stimulates the activity of the COOH-terminal TAD of p300 (p300C-TAD). We have defined the minimal p300C-TAD and show that it is sufficient to respond to deacetylase inhibitors and is a substrate for p300HAT. Finally, we show that acetylated p300 possesses enhanced ability to interact with p53. Taken together, our data suggest that acetylation regulates p300C-TAD and that acetylation of p300/CBP may contribute to the dynamic regulation of their complex formation with various interacting partners.

A transcription factor-binding domain of the coactivator CBP is essential for long-term memory and the expression of specific target genes

Transcriptional activation is a key process required for long-term memory formation. Recently, the transcriptional coactivator CREB-binding protein (CBP) was shown to be critical for hippocampus-dependent long-term memory and hippocampal synaptic plasticity. As a coactivator with intrinsic histone acetyltransferase activity, CBP interacts with numerous transcription factors and contains multiple functional domains. Currently, it is not known which transcription factor-binding domain of CBP is essential for memory storage. Using mice that carry inactivating mutations in the CREB-binding (KIX) domain of the coactivator CBP (CBPKIX/KIX mice), we show that the KIX domain is required for long-term memory storage. These results are the first to identify an in vivo function for the KIX domain of CBP in the brain, and they suggest that KIX-interacting transcription factors recruit CBP histone acetyltransferase activity during long-term memory storage. One such KIX-interacting factor is the transcription factor CREB. Using quantitative real-time RT-PCR, we find that the expression of specific CREB target genes is reduced in the hippocampi of CBPKIX/KIX mice during memory consolidation. The recruitment of the transcriptional coactivator CBP via the KIX domain thus imparts target gene-dependent selectivity to CREB-driven transcriptional regulation, thereby activating genes required for the long-term storage of hippocampus-dependent memory.

Tax-dependent Displacement of Nucleosomes during Transcriptional Activation of Human T-Cell Leukemia Virus Type 1

The human T-cell leukemia virus type 1 (HTLV-1) is integrated into the host cell DNA and assembled into nucleosomes. Within the repressive chromatin environment, the virally encoded Tax protein mediates the recruitment of the coactivators CREB-binding protein/p300 to the HTLV-1 promoter, located within the long terminal repeats (LTRs) of the provirus. These proteins carry acetyltransferase activity that is essential for strong transcriptional activation of the virus in the context of chromatin. Consistent with this, the amino-terminal tails of nucleosomal histones at the viral promoter are acetylated in Tax-expressing cells. We have developed a system in which we transfect Tax into cells carrying integrated copies of the HTLV-1 LTR driving the luciferase gene to analyze changes in "activating" histone modifications at the LTR. Unexpectedly, Tax transactivation led to an apparent reduction of these modifications at the HTLV-1 promoter and downstream region that correlates with a similar reduction in histone H3 and linker histone H1. Micrococcal nuclease protection analysis showed that less LTR-luciferase DNA is nucleosomal in Tax-expressing cells. Furthermore, nucleosome depletion correlated with RNA polymerase II recruitment and loss of SWI/SNF. The M47 Tax mutant, deficient in HTLV-1 transcriptional activation, was also defective for nucleosome depletion. Although this mutant formed complexes with CREB and p300 at the HTLV-1 promoter in vivo, it was unable to mediate RNA polymerase II recruitment or SWI/SNF displacement. These results support a model in which nucleosomes are depleted from the LTR and transcribed region during Tax-mediated transcriptional activation and correlate RNA polymerase II recruitment with nucleosome depletion.

Targeting histone deacetylase 2 in chronic obstructive pulmonary disease treatment

There is increasing evidence that histone acetylation plays a critical role in the regulation of inflammatory genes and in mediating the anti-inflammatory effects of corticosteroids. Inflammatory stimuli through transcription factors, such as NF-κB, recruit co-activator molecules with intrinsic histone acetyltransferase activity, leading to hyperacetylation of core histones and gene activation. Histone deacetylases (HDACs) reverse this process and suppress inflammatory genes. Corticosteroids, the most effective anti-inflammatory drugs so far available, recruit HDAC2 to activated inflammatory gene complexes through an interaction with glucocorticoid receptor and thus switch off activated inflammatory genes. In chronic obstructive pulmonary disease and in asthmatic patients who smoke, there is a reduction in HDAC2 activity and expression, resulting in amplification of inflammation and corticosteroid resistance. Therapeutic strategies to increase HDAC activity may, therefore, be expected to reduce inflammation and restore steroid responsiveness. These strategies include low doses of theophylline or antioxidants and nitric oxide synthase inhibitors. HDACs may be inhibited directly by siRNA and in the future by small-molecule activators may be discovered through high output screening. These drugs may represent a novel approach to treating chronic inflammatory diseases.

Hepatitis C virus core protein recruits nucleolar phosphoprotein B23 and coactivator p300 to relieve the repression effect of transcriptional factor YY1 on B23 gene expression

Hepatitis C virus (HCV) core has a pleiotropic effect on various promoters. In this study, we found that the expression of nucleolar phosphoprotein B23 was enhanced in HCV core-expressing cells and, moreover, HCV core interacts directly with the C-terminal end of B23. Using sucrose gradient centrifugation analysis and immunoprecipitation assays, HCV core was found in a large complex containing B23 and its interacting partner transcription factor YY1. Both B23 and HCV core associated with YY1 in the central GA/GK-rich and C-terminal zinc finger domain. These physical interactions between core, B23, and YY1 led to ternary complex formation that was bound to the YY1 response element. In a transient cotransfection experiment, relief of the trans-suppression activity of YY1 on the YY1-response element-driven reporter by core and B23 was found. This is also true when examining the effects of these three constructs on the B23 promoter-driven reporter. Additionally, chromatin immunoprecipitation assays indicated that a transcriptional activation complex consisting of core, together with B23, p300, and YY1, was recruited to the YY1 response element of B23 promoter, and this probably occurred through complex formation between core and these three cellular transcription regulators. This is different from the situation in the absence of core, where YY1 and histone deacetylase 1, but not B23 and p300, were associated on the YY1 element as the transcription repression complex. Together, our results indicate that HCV core can recruit B23 and p300 to relieve the repression effect of YY1 on B23 promoter activity, a property that requires the intrinsic histone acetyltransferase activity of p300. Thus, because these three core-associated cellular transcription regulators have a multitude of cellular interacting proteins and are involved in a versatility of cellular processes, the complex formation described here may partially account for the pleiotropic effects of core protein on gene expression and cellular function in HCV-infected cells.

Akt Phosphorylation of p300 at Ser-1834 Is Essential for Its Histone Acetyltransferase and Transcriptional Activity

The PI3K/Akt pathway plays a critical role in the regulation of gene expression induced by numerous stimuli. p300, a transcriptional coactivator, acts in concert with transcription factors to facilitate gene expression. Here, we show that Akt is activated and translocated to the nucleus in response to tumor necrosis factor alpha. Nuclear Akt associates with p300 and phosphorylates its Ser-1834 both in vivo and in vitro. The phosphorylation induces recruitment of p300 to the ICAM-1 promoter, leading to the acetylation of histones in chromatin and association with the basal transcriptional machinery RNA polymerase II. These two events facilitate ICAM-1 gene expression and are abolished by the p300 S1834A mutant, inhibitors of PI3K/Akt, or small interfering RNA of Akt. Histone acetylation is attributed to the Akt-enhanced intrinsic histone acetyltransferase (HAT) activity of p300 and its association with another HAT, p/CAF. Our study provides a new insight into the molecular mechanism by which Akt promotes the transcriptional potential of p300.

Napthalimidobenzamide DB-51630: a novel DNA binding agent inducing p300 gene expression and exerting a potent anti-cancer activity

Control of gene expression by small molecule compounds is a novel therapeutic strategy for cancer and usually it requires the presence of specific molecular recognition. The development of the compounds preferentially binding to the specific DNA sequence is one of the potential but very difficult approaches in this strategy. We designed and synthesized novel napthalimidobenzamide derivatives and analyzed their binding preferences to oligonucleotides by EtBr-displacement assay with DNA sequences, being essential fragments of the genes. To test whether these compounds modify the expression of specific genes, we analyzed the effect on the gene expression in AZ521 cells by differential display analysis using the compounds showing different characteristics in the recognition of specific DNA sequence. Among them, DB-51630, which showed approximately 350 times higher preferential binding to GC-repeats than to the AT and AA-repeating oligomers, caused the induction of a specific mRNA. The genetic sequence was identified to be the p300 gene by sequencing of the cloned cDNA. The p300 is a transcriptional co-activator protein that acts with other nuclear proteins in various cell differentiation and signal transduction pathways. This protein has intrinsic histone acetyltransferase activity and may act on chromatin directly to facilitate transcription. The increase of the amount of p300 mRNA increased after DB-51630 treatment by real time RT-PCR and Northern blot analysis. DB-51630 inhibited cell growth in various cancer cell lines at nanomolar range of concentrations, whereas p300 mRNA induction was observed at sub-nanomolar concentrations and the maximal induction occurred 8 h after DB-51630 treatment. In contrast, anti-cancer drugs such as doxorubicin, vincristine, cisplatin, etoposide, and actinomycin D did not increase p300 transcription. DB-51630 revealed potent anti-cancer activity against human solid tumor xenografts. Thus, we demonstrated the anti-cancer activity of DB-51630, which interacts with a specific DNA sequence, thereby inducing p300 gene expression and exhibited significant anti-cancer activity in human tumor xenografts. Furthermore, such compounds that bind to specific DNA sequences may not only control the expression of specific genes but also exert other mechanisms in the anti-cancer effect than those of classical DNA binding drugs.

What's right with my mouse model? New insights into the molecular and cellular basis of cognition from mouse models of Rubinstein-Taybi Syndrome: Table 1.

What's right with my mouse model? New insights into the molecular and cellular basis of cognition from mouse models of Rubinstein-Taybi Syndrome: Table 1.

Histone acetylation and deacetylation: importance in inflammatory lung diseases

Inflammatory lung diseases are characterised by increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as nuclear factor-kappa B. Gene expression is regulated by acetylation of core histones through the action of coactivators, such as CREB-binding protein, with intrinsic histone acetyltransferase (HAT) activity. Conversely, gene repression is mediated via histone deacetylases (HDACs) and other corepressors. In asthma, there is an increase in HAT activity and some reduction in HDAC activity, which is restored by corticosteroid therapy. Corticosteroids switch off inflammatory genes in asthma through the inhibition of HAT activity and by the recruitment of HDAC2 to the activated inflammatory gene complex. In chronic obstructive pulmonary disease, there is a reduction in HDAC2 activity and expression, which may account for the amplified inflammation and resistance to the actions of corticosteroids. The reduction in HDAC2 may be secondary to oxidative and nitrative stress as a result of cigarette smoking and severe inflammation, and may also occur in severe asthma, smoking asthmatic patients and cystic fibrosis. Similar mechanisms may also account for the steroid resistance seen with latent adenovirus infections. The reduction in histone deacetylase activity can be restored by theophylline, which may be able to reverse steroid resistance in chronic obstructive pulmonary disease and other inflammatory diseases.

SAGA unveiled

Transcriptional regulation in eukaryotes is intimately coupled to chromatin dynamics. The SAGA (Spt-Ada-Gcn5) histone acetyltransferase (HAT) complex of Saccharomyces cerevisiae is a multi-subunit co-factor for RNA polymerase II transcription. However, not all gene activation events require its intrinsic HAT activity. In addition, SAGA subunits can also restrict gene transcription. The recently published structural model from the laboratories of Fred Winston and Patrick Schultz of the SAGA complex provides a framework to rationalize these findings and to direct further investigation of this crucial transcriptional co-factor.

Characterization of the Histone Acetyltransferase (HAT) Domain of a Bifunctional Protein with Activable O-GlcNAcase and HAT Activities

Histones and transcription factors are regulated by a number of post-translational modifications that in turn regulate the transcriptional activity of genes. These modifications occur in large, multisubunit complexes. We have reported previously that mSin3A can recruit O-GlcNAc transferase (OGT) along with histone deacetylase into such a corepressor complex. This physical association allows OGT to act cooperatively with histone deacetylation in gene repression by catalyzing the O-GlcNAc modification on specific transcription factors to inhibit their activity. For rapid, reversible gene regulation, the enzymes responsible for the converse reactions must be present. Here, we report that O-GlcNAcase, which is responsible for the removal of O-GlcNAc additions on nuclear and cytosolic proteins, possesses intrinsic histone acetyltransferase (HAT) activity in vitro. Free as well as reconstituted nucleosomal histones are substrates of this bifunctional enzyme. This protein, now termed NCOAT (nuclear cytoplasmic O-GlcNAcase and acetyltransferase) has a typical HAT domain that has both active and inactive states. This finding demonstrates that NCOAT may be regulated to reduce the state of glycosylation of transcriptional activators while increasing the acetylation of histones to allow for the concerted activation of eukaryotic gene transcription.

Transcriptional Regulation of Dentin Matrix Protein 1 by JunB and p300 during Osteoblast Differentiation

Dentin matrix protein 1 (DMP1) is an acidic noncollagenous protein localized specifically in the mineralized matrix of bone and dentin. Expression analyses demonstrate that DMP1 is differentially regulated in osteoblasts and odontoblasts. Earlier we have reported on the transcriptional regulation of DMP1 by c-Fos and c-Jun (AP-1) transcription factors. Results from earlier study indicate that c-Fos and c-Jun play an important role in early osteoblast differentiation, whereas they do not have a significant effect on the terminally differentiated osteoblasts. In this paper, we demonstrate a regulatory mechanism by which JunB transcriptionally controls the expression of DMP1 during osteoblast differentiation. The cooperative interaction of JunB with p300 has been shown to dramatically modulate the DMP1 promoter activity during mineralization. Immunoprecipitation and chromatin immunoprecipitation analysis demonstrate the interaction of JunB and p300 in vivo. Further, phosphorylation of JunB at Ser-79 was found to be essential for its interaction with p300. Intrinsic histone acetyltransferase activity of p300 also plays a critical role in regulating DMP1 gene expression.

Redox modulation of chromatin remodeling: impact on histone acetylation and deacetylation, NF-κB and pro-inflammatory gene expression

Reactive oxygen species (ROS), either directly or via the formation of lipid peroxidation products, such as 4-hydroxy-2-nonenal, acrolein and F 2-isoprostanes, may play a role in enhancing inflammation through the activation and phosphorylation of stress kinases (JNK, ERK, p38) and redox-sensitive transcription factors such as NF-κB and AP-1. This increases the expression of genes regulating a battery of distinct pro-inflammatory mediators. Acetylation by histone acetyltransferase (HAT) of specific lysine residues on the N-terminal tail of core histones, results in uncoiling of the DNA and increased accessibility to transcription factor binding. In contrast, histone deacetylation by histone deacetylase (HDAC) represses gene transcription by promoting DNA winding thereby limiting access to transcription factors. Oxidative stress activates NF-κB resulting in expression of pro-inflammatory mediators through the activation of intrinsic HAT activity on co-activator molecules. In addition, oxidative stress also inhibits HDAC activity and in doing so enhances inflammatory gene expression which leads to a chronic inflammatory response. Oxidative stress can also increase complex formation between the co-activator CBP/p300 and the p65 subunit of NF-κB suggesting a further role of oxidative stress in chromatin remodeling. The antioxidant and/or anti-inflammatory effects of thiol molecules (glutathione, N-acetyl- l-cysteine and N-acystelyn), dietary polyphenols (curcumin-diferuloylmethane and resveratrol), the bronchodilator theophylline and glucocorticoids have all been shown to play a role in either controlling NF-κB activation or chromatin remodeling through modulation of HDAC activity and subsequently inflammatory gene expression in lung epithelial cells. Thus, oxidative stress regulates both signal transduction and chromatin remodeling which in turn impacts on pro-inflammatory responses in the lungs.

Implications of transcriptional coactivator CREB binding protein complexes in rheumatoid arthritis

Transcriptional coactivators have crucial roles in eukaryotic transcription. It has been suggested that one of the coactivators, cAMP response element binding protein (CREB) binding protein (CBP), regulates gene expression with a number of transcription factors via two mechanisms. One is the recruitment of general transcriptional machinery to the promoters. The other is its intrinsic and associated histone acetyltransferase (HAT) activity, which increases the accessibility of the activator to DNA, and the acetylation of nonhistone proteins. Rheumatoid arthritis (RA) is characterized by the inflammation and proliferation of synovium, leading to the destruction of articular cartilage and bone. To understand the pathogenesis of RA, we focused the transcription mechanism through CBP in synoviocytes and chondrocytes. We identified Notch-1 in synoviocytes and p34(SEI-1) in chondrocytes as CBP binding proteins by yeast two-hybrid screening. It was also suggested that the acetylation of p53 could repress transactivation in RA synoviocytes. These associations may regulate proliferation and apoptosis. This study suggests that regulation of the coactivator could become a novel strategy for RA therapy.