Acetylation of β-catenin by CREB-binding protein (CBP)

University of Cambridge, Cambridge, England, United Kingdom
Journal of Biological Chemistry (Impact Factor: 4.57). 08/2002; 277(28):25562-7. DOI: 10.1074/jbc.M201196200
Source: PubMed


Acetylation controls the activity of numerous proteins involved in regulating gene transcription as well as many other cellular
processes. In this report we show that the CREB-binding protein (CBP) acetyltransferase acetylates β-catenin protein in vivo. β-Catenin is a central component of the Wnt signaling pathway, which is of key importance in development as well as being
heavily implicated in a variety of human cancers. We show that the CBP-mediated acetylation of β-catenin occurs at a single
site, lysine 49. Importantly, this lysine is frequently found mutated in cancer and is in a region of importance to the regulation
of β-catenin. We show that mutation of this site leads specifically to an increase in the ability of β-catenin to activate
the c-myc gene but not other β-catenin-regulated genes. This suggests that acetylation of β-catenin is involved in regulating Wnt signaling
in a promoter-specific fashion.

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    • "Some b-catenin transcriptional co-activators bind N-terminally to the first ARM repeats, such as BCL9 (Kramps et al, 2002; Mosimann et al, 2009). Many of the transcriptional co-activators of b-catenin affect chromatin structure by modifying histones, such as the histone acetyltransferases CBP (Wolf et al, 2002), p300 (Levy et al, 2004), and Tip60 (Kim et al, 2005a), or by rearranging nucleosomes, such as SWI/ SNF and ISWI (Song et al, 2009). Other binding partners promote the association of TCF/b-catenin with the RNA polymerase II complex such as members of the Mediator complex (Kim et al, 2006; Carrera et al, 2008) and components of the Paf1 complex (Mosimann et al, 2006; Parker et al, 2008). "
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    ABSTRACT: Active canonical Wnt signaling results in recruitment of β-catenin to DNA by TCF/LEF family members, leading to transcriptional activation of TCF target genes. However, additional transcription factors have been suggested to recruit β-catenin and tether it to DNA. Here, we describe the genome-wide pattern of β-catenin DNA binding in murine intestinal epithelium, Wnt-responsive colorectal cancer (CRC) cells and HEK293 embryonic kidney cells. We identify two classes of β-catenin binding sites. The first class represents the majority of the DNA-bound β-catenin and co-localizes with TCF4, the prominent TCF/LEF family member in these cells. The second class consists of β-catenin binding sites that co-localize with a minimal amount of TCF4. The latter consists of lower affinity β-catenin binding events, does not drive transcription and often does not contain a consensus TCF binding motif. Surprisingly, a dominant-negative form of TCF4 abrogates the β-catenin/DNA interaction of both classes of binding sites, implying that the second class comprises low affinity TCF-DNA complexes. Our results indicate that β-catenin is tethered to chromatin overwhelmingly through the TCF/LEF transcription factors in these three systems.
    Full-text · Article · Jan 2014 · The EMBO Journal
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    • "In this case, however, acetylation affects the cytoplasmic/nuclear distribution of Pop-1 [41]. In vertebrates, the CBP-catalyzed acetylation of β-catenin increases its affinity for TCF4 [42], [43]. Furthermore, as in Drosophila, CBP and p300 function as crucial transcriptional cofactors of β-catenin [44]–[47]. "
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    ABSTRACT: The members of the TCF/LEF family of DNA-binding proteins are components of diverse gene regulatory networks. As nuclear effectors of Wnt/β-catenin signaling they act as assembly platforms for multimeric transcription complexes that either repress or activate gene expression. Previously, it was shown that several aspects of TCF/LEF protein function are regulated by post-translational modification. The association of TCF/LEF family members with acetyltransferases and deacetylases prompted us to investigate whether vertebrate TCF/LEF proteins are subject to acetylation. Through co-expression with p300 and CBP and subsequent analyses using mass spectrometry and immunodetection with anti-acetyl-lysine antibodies we show that TCF4 can be acetylated at lysine K150 by CBP. K150 acetylation is restricted to TCF4E splice variants and requires the simultaneous presence of β-catenin and the unique TCF4E C-terminus. To examine the functional consequences of K150 acetylation we substituted K150 with amino acids representing the non-acetylated and acetylated states. Reporter gene assays based on Wnt/β-catenin-responsive promoter regions did not indicate a general role of K150 acetylation in transactivation by TCF4E. However, in the presence of CBP, non-acetylatable TCF4E with a K150R substitution was more susceptible to inhibition by the HBP-1 repressor protein compared to wild-type TCF4E. Acetylation of K150 using a bacterial expression system or amino acid substitutions at K150 alter the electrophoretic properties of TCF4E::DNA complexes. This result suggests that K150 acetylation leads to a conformational change that may also represent the mechanism whereby acetylated TCF4E acquires resistance against HBP1. In summary, TCF4 not only recruits acetyltransferases but is also a substrate for these enzymes. The fact that acetylation affects only a subset of TCF4 splice variants and is mediated preferentially by CBP suggests that the conditional acetylation of TCF4E is a novel regulatory mechanism that diversifies the transcriptional output of Wnt/β-catenin signaling in response to changing intracellular signaling milieus.
    Full-text · Article · Apr 2013 · PLoS ONE
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    • "β-catenin activity is also regulated through interaction with two nuclear transcriptional co-activators: Cyclic AMP responsive element binding protein (CBP) and its highly related paralog p300. Both CBP and p300 are transcriptional co-activator proteins that can acetylate histones and non-histone proteins such as β-catenin [26]–[29]. Both proteins regulate gene transcription through protein-protein interactions with transcription factors and chromatin-remodeling complexes [30]. "
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    ABSTRACT: Fibroblast Growth Factor (FGF)-10 promotes the proliferation and survival of murine hepatoblasts during early stages of hepatogenesis through a Wnt-β-catenin dependent pathway. To determine the mechanism by which this occurs, we expanded primary culture of hepatoblasts enriched for progenitor markers CD133 and CD49f from embryonic day (E) 12.5 fetal liver and an established tumor initiating stem cell line from Mat1a−/− livers in media conditioned with recombinant (r) FGF10 or rFGF7. FGF Receptor (R) activation resulted in the downstream activation of MAPK, PI3K-AKT, and β-catenin pathways, as well as cellular proliferation. Additionally, increased levels of nuclear β-catenin phosphorylated at Serine-552 in cultured primary hepatoblasts, Mat1a−/− cells, and also in ex vivo embryonic liver explants indicate AKT-dependent activation of β-catenin downstream of FGFR activation; conversely, the addition of AKT inhibitor Ly294002 completely abrogated β-catenin activation. FGFR activation-induced cell proliferation and survival were also inhibited by the compound ICG-001, a small molecule inhibitor of β-catenin-CREB Binding Protein (CBP) in hepatoblasts, further indicating a CBP-dependent regulatory mechanism of β-catenin activity. Conclusion: FGF signaling regulates the proliferation and survival of embryonic and transformed progenitor cells in part through AKT-mediated activation of β-catenin and downstream interaction with the transcriptional co-activator CBP.
    Full-text · Article · Nov 2012 · PLoS ONE
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