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HAT cofactor TRRAP mediates beta-catenin ubiquitination on the chromatin and the regulation of the canonical Wnt pathway

Finkbeiner, Martin G
Sawan, Carla
Ouzounova, Maria
Herceg, Zdenko
Published in Cell cycle. 2008, vol. 7, no. 24, p. 3908-14
Abstract The Wnt pathway is a key regulator of embryonic development and stem cell self-renewal, and hyperactivation of the Wnt signalling is associated with many human cancers. The central player in the Wnt pathway is beta-catenin, a cytoplasmic protein whose function is tightly controlled by ubiquitination and degradation, however the precise regulation of beta-catenin stability/degradation remains elusive. Here, we report a new mechanism of beta-catenin ubiquitination acting in the context of chromatin. This mechanism is mediated by the histone acetyltransferase (HAT) complex component TRRAP and Skp1, an invariable component of the Skp-Cullin-F-box (SCF) ubiquitin ligase complex. TRRAP interacts with Skp1/SCF and mediates its recruitment to beta-catenin target promoter in chromatin. TRRAP deletion leads to a reduced level of beta-catenin ubiquitination, lower degradation rate and accumulation of beta-catenin protein. Furthermore, recruitment of Skp1 to chromatin and ubiquitination of chromatin-bound beta-catenin are abolished upon TRRAP knock-down, leading to an abnormal retention of beta-catenin at the chromatin and concomitant hyperactivation of the canonical Wnt pathway. These results demonstrate that there is a distinct regulatory mechanism for beta-catenin ubiquitination/ destruction acting in the nucleus which functionally complements cytoplasmic destruction of beta-catenin and prevents its oncogenic stabilization and chronic activation of the canonical Wnt pathway.
Keywords Adaptor Proteins, Signal Transducing/metabolismCell LineChromatin/metabolismGene Knockdown TechniquesHistone Acetyltransferases/metabolismHumansModels, BiologicalNuclear Proteins/metabolismRNA, Small InterferingS-Phase Kinase-Associated Proteins/metabolismSignal TransductionUbiquitinationWnt Proteins/metabolismBeta Catenin/metabolism
PMID: 19066453
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FINKBEINER, Martin G et al. HAT cofactor TRRAP mediates beta-catenin ubiquitination on the chromatin and the regulation of the canonical Wnt pathway. In: Cell cycle, 2008, vol. 7, n° 24, p. 3908-14. doi: 10.4161/cc.7.24.7354

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Deposited on : 2014-12-17

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