Acetylation of β-catenin by CREB-binding protein (CBP)
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.
- SourceAvailable from: Jurian Schuijers
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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). "
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.The EMBO Journal 01/2014; 33(2). DOI:10.1002/embj.201385358 · 10.75 Impact Factor
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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). "
ABSTRACT: β-Catenin (Armadillo in Drosophila) is a multitasking and evolutionary conserved molecule that in metazoans exerts a crucial role in a multitude of developmental and homeostatic processes. More specifically, β-catenin is an integral structural component of cadherin-based adherens junctions, and the key nuclear effector of canonical Wnt signalling in the nucleus. Imbalance in the structural and signalling properties of β-catenin often results in disease and deregulated growth connected to cancer and metastasis. Intense research into the life of β-catenin has revealed a complex picture. Here, we try to capture the state of the art: we try to summarize and make some sense of the processes that regulate β-catenin, as well as the plethora of β-catenin binding partners. One focus will be the interaction of β-catenin with different transcription factors and the potential implications of these interactions for direct cross-talk between β-catenin and non-Wnt signalling pathways.The EMBO Journal 05/2012; 31(12):2714-36. DOI:10.1038/emboj.2012.150 · 10.75 Impact Factor
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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 . 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 . "
ABSTRACT: Wnt proteins are a large family of secreted glycoproteins. Wnt proteins bind to the Frizzled receptors and LRP5/6 co-receptors, and through stabilizing the critical mediator beta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. Deregulation of the canonical Wnt/beta-catenin signaling pathway, mostly by inactivating mutations of the APC tumor suppressor, or oncogenic mutations of beta-catenin, has been implicated in colorectal tumorigenesis. Although oncogenic mutations of beta-catenin have only been discovered in a small fraction of non-colon cancers, elevated levels of beta-catenin protein, a hallmark of activated canonical Wnt pathway, have been observed in most common forms of human malignancies, indicating that activation of this pathway may play an important role in tumor development. Over the past 15 years, our understanding of this signaling pathway has significantly improved with the identification of key regulatory proteins and the important downstream targets of beta-catenin/Tcf transactivation complex. Given the fact that Wnt/beta-catenin signaling is tightly regulated at multiple cellular levels, the pathway itself offers ample targeting nodal points for cancer drug development. In this review, we discuss some of the strategies that are being used or can be explored to target key components of the Wnt/beta-catenin signaling pathway in rational cancer drug discovery.Current Cancer Drug Targets 01/2005; 4(8):653-71. DOI:10.2174/1568009043332709 · 3.58 Impact Factor