Cell-Type-Specific Function of BCL9 Involves a Transcriptional Activation Domain That Synergizes with β-Catenin

Abstract

Transcriptional regulation by the canonical Wnt pathway involves the stabilization and nuclear accumulation of β-catenin, which assembles with LEF1/TCF transcription factors and cofactors to activate Wnt target genes. Recently, the nuclear β-catenin complex has been shown to contain BCL9, which interacts with β-catenin and recruits Pygopus as a transcriptional coactivator. However, the presumed general functions of Pygopus and BCL9, which has been proposed to act as a scaffolding protein for Pygopus, have been challenged by the rather specific and modest developmental defects of targeted inactivations of both the Pygo1 and the Pygo2 genes. Here, we analyze the function of BCL9 in transcriptional activation by β-catenin. We find that BCL9 acts in a cell-type-specific manner and, in part, independent of Pygopus. We show that BCL9 itself contains a transcriptional activation domain in the C terminus, which functionally synergizes in lymphoid cells with the C-terminal transactivation domain of β-catenin. Finally, we identify amino acids in the transactivation domain of β-catenin that are important for its function and association with the histone acetyltransferases CBP/p300 and TRRAP/GCN5. Thus, BCL9 may serve to modulate and diversify the transcriptional responses to Wnt signaling in a cell-type-specific manner.

ACKNOWLEDGMENTS

We are grateful to K. Basler for sharing a BCL9 cDNA construct. We thank R. Kemler for providing floxed β-catenin ES cells. We thank A. Hecht for donating several plasmids. We thank L. Tora for anti-TRRAP and anti-GCN5 antibodies. E. Kremmer we thank for expert help in the generation of BCL9 antibodies. We thank T. Stehle for the opportunity to use his spectropolarimeter. We thank H. J. Fehling for the supply with a Cre-EGFP construct.

This work was supported by the funds of the Max Planck Society and a grant from the German Research Foundation (DFG).