Article

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

ABSTRACT 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 beta-catenin protein in vivo. beta-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 beta-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 beta-catenin. We show that mutation of this site leads specifically to an increase in the ability of beta-catenin to activate the c-myc gene but not other beta-catenin-regulated genes. This suggests that acetylation of beta-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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    • "b-Catenin can also be acetylated by CBP at Lys49; point mutations that block acetylation result in ectopic transcriptional activation of the target gene c-myc, an effect that seems to be specific to this target, since others were unaffected (Wolf et al, 2002). Interestingly, this lysine residue is often found mutated in various cancers (Wolf et al, 2002). In contrast, modification of Lys345 by p300 has a broader effect and increases the affinity of b-catenin for TCF; b-catenin acetylated at Lys345 was strongly enriched in the colon cancer cells with hyperactivated Wnt/b-catenin transcription (Lévy et al, 2004). "
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    • "Upon entering the nucleus, β-catenin binds to the transcription factors Tcf/LEF, which promotes the expression of Tcf-regulated genes. In addition, β-catenin gets acetylated by CBP (CREB-Binding Protein) to enhance transactivation at the c-Myc promoter region [158]. The human Tcf/LEF family of transcription factors consists of Tcf-1, LEF-1, Tcf-3, and Tcf-4, which all contain an 80 amino acid high-mobility group box (HMG) that binds DNA [159]. "
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