Disease relevance of CREBBP

• t(10;16)(q22;p13) and MORF-CREBBP fusion is a recurrent event in acute myeloid leukemia [1].
• DNA sequencing of CREBBP demonstrates mutations in 56% of patients with Rubinstein-Taybi syndrome (RSTS) and in another patient with incomplete RSTS [2].
• This provides a new mechanism for inhibition of the IFN-alpha-activated antiviral response by E1A, and supports the view that E1A binding to p300/CBP has functional significance for adenovirus replication in its natural host [3].
• Expanded polyglutamine repeats specifically interfere with CBP-activated gene transcription, and overexpression of CBP rescued polyglutamine-induced neuronal toxicity [4].
• Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300 [5].
• In a human colorectal cancer cell line, we show that CBP and p300 can inhibit Wnt signaling and demonstrate that human p300 can bind directly to TCF4 in vitro [6].

Psychiatry related information on CREBBP

• Expanded polyglutamine repeats have been proposed to cause neuronal degeneration in Huntington's disease (HD) and related disorders, through abnormal interactions with other proteins containing short polyglutamine tracts such as the transcriptional coactivator CREB binding protein, CBP [4].
• We studied a mouse model of the haploinsufficiency form of Rubinstein-Taybi syndrome (RTS), an inheritable disorder caused by mutations in the gene encoding the CREB binding protein (CBP) and characterized by mental retardation and skeletal abnormalities [7].
• The role of these proteins in human disease coupled with biochemical evidence suggests that CBP and p300 are tumor suppressor proteins essential in cell-cycle control, cellular differentiation and human development [8].
• Our recent work suggests that CBP loss of function could also be involved in Alzheimer's disease and amyotrophic lateral sclerosis [9].
• Differential Role for CBP and p300 CREB-Binding Domain in Motor Skill Learning [10].

High impact information on CREBBP

• N-Cad/CTF2 binds the transcription factor CBP and promotes its proteasomal degradation, inhibiting CRE-dependent transactivation [11].
• Mutations in PS-1 associated with Alzheimer's disease interfere with CBP proteolysis, leading to abnormal transcription [12].
• In this issue of Cell, Marambaud et al. report that PS-1 cleaves the cell adhesion molecule N-cadherin, releasing a C-terminal fragment that promotes degradation of the transcriptional coactivator CBP [12].
• Acetylation of histones by p300/CBP and PCAF is considered to be a critical step in transcriptional regulation [13].
• Nucleosome acetylation in turn facilitates SWI/SNF recruitment by CBP, resulting in chromatin remodeling [14].

Chemical compound and disease context of CREBBP

• The rescue function mapped to the cysteine-histidine rich domain CH3, a region of p300/CBP that we found to interact directly with the conserved COOH-terminal activation domain (AF-2) of ER-alpha. p300 and ER-alpha were also found to interact in vivo and to colocalize within the nucleus in breast cancer cells [15].
• Intracellular Listeria induced time-dependent acetylation (lysine 8) of histone H4 and phosphorylation/acetylation (serine 10/lysine 14) of histone H3 globally and at the il8 promoter in HUVEC, as well as recruitment of the histone acetylase CREB-binding protein [16].
• Taken together, our findings demonstrate the selective enhancement of agonistic action of the anti-androgen hydroxyflutamide by the transcriptional co-activator CBP, which is a new, potentially relevant mechanism contributing to the acquisition of therapy resistance in prostate cancer [17].
• In Exp. 1, infusion of antisense oligodeoxynucleotides to SRC-1 and CBP mRNA into the VMN decreased lordosis intensity in rats treated with E alone, suggesting that these coactivators modulate ER-mediated female sexual behavior [18].
• 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 [19].

Biological context of CREBBP

• Accordingly, we screened a panel of 103 cell lines for loss of heterozygosity and found 35 and 51% LOH for the CREBBP and EP300 loci, respectively [20].
• Here, we report a new case with the MORF-CREBBP fusion in an 84-year-old patient diagnosed with AML M5b, in which the t(10;16)(q22;p13) was the only cytogenetic aberration [1].
• We report not only the highest detection rate (56.6%) of CREBBP mutations in patients with RSTS to date, but also the second missense mutation (N1978S) in a patient with moderate or incomplete RSTS [2].
• A cDNA probe for the mouse CREB binding protein was used to localize this gene (CREBBP) to human chromosome 16p13.3 by fluorescence in situ hybridization (FISH) [21].
• A panel of five cosmids spanning the human cyclic AMP-responsive element binding (CREB) binding protein (CREBBP or CBP) gene in terms of RT100, RT102, RT191, RT203 and RT166 (Leiden, the Netherlands) were used for fluorescence in situ hybridization on the metaphases of those patients [22].

Anatomical context of CREBBP

• Analysis of genetic stability at the EP300 and CREBBP loci in a panel of cancer cell lines [20].
• A reconstitution experiment illustrated that optimum CREB-CBP interaction and CREB trans-activation were attained when these three kinase pathways were simultaneously activated in T cells [23].
• Control of CREB-binding protein signaling by nuclear fibroblast growth factor receptor-1: a novel mechanism of gene regulation [24].
• Cooperative interaction of EWS with CREB-binding protein selectively activates hepatocyte nuclear factor 4-mediated transcription [25].
• In transfected HeLa cells, we show that the full-length ERalpha can interact physically and functionally with p160/SRCs and CBP in the absence of ligand and that mutation of Ser104/106/118 affects these interactions [26].

Associations of CREBBP with chemical compounds

• Thus, polyglutamine-mediated interference with CBP-regulated gene transcription may constitute a genetic gain of function, underlying the pathogenesis of polyglutamine disorders [4].
• We further present the three-dimensional nuclear magnetic resonance structure of the CBP bromodomain in complex with a lysine 382-acetylated p53 peptide [27].
• Amino acid replacement in the sequences of CADs revealed a specific cysteine to be essential for their hypoxia-inducible interaction with CBP [5].
• Control of CBP co-activating activity by arginine methylation [28].
• One class of the nuclear receptor AF-2 coactivator complexes contains the SRC-1/TIF2 family, CBP/p300 and an RNA coactivator, SRA [29].

Physical interactions of CREBBP

• Here we show that the human PR also interacts with p300/CBP-associated factor in vitro [30].
• Whereas both the N terminus and ligand-binding domain of AR can interact with CBP, a short region in the N terminus of CBP is required for these interactions [31].
• The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein [32].
• 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 [24].
• The coactivator of transcription CREB-binding protein interacts preferentially with the glycosylated form of Stat5 [33].

Enzymatic interactions of CREBBP

• Using purified components, we found that the MLL activation domain facilitated the binding of CBP to phosphorylated CREB [34].

Co-localisations of CREBBP

• Finally, we show that Zta and CBP colocalize to viral immediate-early promoters in vivo and that overexpression of Zta leads to a robust increase in H3 and H4 acetylation at various regions of the EBV genome in vivo [35].
• PIMT appeared to be co-localized in the nucleus with CBP, p300, and PBP [36].
• The NeuroD1/BETA2 sequences essential for insulin gene transcription colocalize with those necessary for neurogenesis and p300/CREB binding protein binding [37].

Regulatory relationships of CREBBP

• CBP enhanced androgen receptor (AR)-dependent transcription under transient transfection conditions in CV-1 cells [38].
• We now describe that BRCA1-mediated transactivation is enhanced by p300/CBP (CREB binding protein) and that this effect was suppressed by the adenovirus E1A oncoprotein [39].
• Interestingly, addition of purified CBP to the nuclear extracts of T47D cells markedly stimulated progesterone- and PR-dependent transcription from a nucleosome-free, progesterone response element (PRE)-linked reporter DNA template [40].
• Taken together, these results demonstrate that CBP-induced acetylation of AFX is a novel modification mechanism by which AFX keeps the transcriptional activity mitigating in the nucleus [41].
• We demonstrated that the transactivation function of KLF5 was enhanced by CREB-binding protein (CBP) and blocked by wild-type but not mutant E1A [42].

Other interactions of CREBBP

• ACTR also recruits two other nuclear factors, CBP and P/CAF, and thus plays a central role in creating a multisubunit coactivator complex [43].
• Cooperation of Stat2 and p300/CBP in signalling induced by interferon-alpha [3].
• CREB-binding protein in androgen receptor-mediated signaling [38].
• Ectopic expression of CBP or the related coactivator, p300, enhanced ER transcriptional activity by up to 10-fold in a receptor- and DNA-dependent manner [44].
• CBP/p300 interact with and function as transcriptional coactivators of BRCA1 [39].
• Such phosphorylation enhances NF-kappaB-mediated gene expression and suppresses p53-mediated gene expression by switching the binding preference of CBP from p53 to NF-kappaB, thus promoting cell growth [45].
• We report three three-dimensional solution structures of the bromodomains of the human transcriptional coactivators CREB-binding protein (CBP) and p300/CBP-associated factor (PCAF) bound to peptides derived from histone acetylation sites at lysines 36 and 9 in H3, and lysine 20 in H4 [46].

Analytical, diagnostic and therapeutic context of CREBBP

• Analysis of CBP (CREBBP) gene deletions in Rubinstein-Taybi syndrome patients using real-time quantitative PCR [47].
• 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 [48].
• Moreover, double and triple immunofluorescence analyses revealed the presence of CBP, p300, and pol II in a subset of promyelocytic leukemia (PML) bodies [48].
• Western blotting and amino-terminal protein sequencing indicated that all lysine residues in the H3 and H4 amino-terminal tails were acetylated by CBP and enhanced by the addition of Zta [35].
• It abolished the HAT activity of CBP and the ability of CBP to transactivate cyclic AMP-response element binding protein (CREB), in HAT assays and in microinjection experiments, respectively [49].

References