Acetylation of β-Catenin by p300 Regulates β-Catenin-Tcf4 Interaction

Abstract

Lysine acetylation modulates the activities of nonhistone regulatory proteins and plays a critical role in the regulation of cellular gene transcription. In this study, we showed that the transcriptional coactivator p300 acetylated β-catenin at lysine 345, located in arm repeat 6, in vitro and in vivo. Acetylation of this residue increased the affinity of β-catenin for Tcf4, and the cellular Tcf4-bound pool of β-catenin was significantly enriched in acetylated form. We demonstrated that the acetyltransferase activity of p300 was required for efficient activation of transcription mediated by β-catenin/Tcf4 and that the cooperation between p300 and β-catenin was severely reduced by the K345R mutation, implying that acetylation of β-catenin plays a part in the coactivation of β-catenin by p300. Interestingly, acetylation of β-catenin had opposite, negative effects on the binding of β-catenin to the androgen receptor. Our data suggest that acetylation of β-catenin in the arm 6 domain regulates β-catenin transcriptional activity by differentially modulating its affinity for Tcf4 and the androgen receptor. Thus, our results describe a new mechanism by which p300 might regulate β-catenin transcriptional activity.

We thank O. Bischof, K. T. Jeang, J. G. Judde, and R. Kiernan for critical reading of the manuscript. We are grateful to P. Tiollais and A. Dejean for constant interest in this work. We also thank G. Castoria, H. Clevers, S. Emiliani, and Y. Nakatani for kindly providing the constructs used in this study.

This work was supported in part by grant 4395 from the Association pour la Recherche sur le Cancer (ARC). L.L. and Y.W. were funded by an ARC fellowship. C.L. was funded by an ENS fellowship.