Nucleic Acids Research Advance Access originally published online on September 20, 2006
Nucleic Acids Research 2006 34(18):5052-5059; doi:10.1093/nar/gkl652
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Nucleic Acids Research, 2006, Vol. 34, No. 18 5052-5059
© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Interplay of Fli-I and FLAP1 for regulation of ß-catenin dependent transcription
Department of Biochemistry and Molecular Biology, University of Southern California 1333 San Pablo Avenue, MCA 51A, Los Angeles, CA 90089, USA
*To whom correspondence should be addressed. Tel: +1 323 442 1145; Fax: +1 323 442 1224; Email: stallcup{at}usc.edu
Received June 8, 2006. Revised August 18, 2006. Accepted August 24, 2006.
ß-catenin mediates Wnt/wingless signaling and transcriptional activation by lymphocyte enhancer binding factor 1/T cell factor (LEF1/TCF) proteins with the assistance of multiple coregulators, including positive cofactors like p300/CBP and negative cofactors like HDACs. We previously demonstrated that a developmentally essential protein, Flightless-I (Fli-I), serves as a coactivator for nuclear receptor-mediated transcription. To further understand the action mechanism of Fli-I, we investigated the functional roles of Fli-I and Fli-I leucine rich repeat associated protein 1 (FLAP1) in transcriptional activation by ß-catenin and LEF1/TCF. ß-catenin-dependent transcription was activated by exogenous FLAP1 but inhibited by Fli-I. Reduction of endogenous FLAP1 levels compromised transcriptional activation by LEF1/TCF, ß-catenin and the p160 coactivator GRIP1. FLAP1 interacted directly with ß-catenin, GRIP1 and p300 and enhanced their activity. Furthermore, FLAP1 was strongly synergistic with p300 in supporting transcriptional activation by ß-catenin and LEF1/TCF, but Fli-I disrupted the synergy of FLAP1 with p300 and ß-catenin. Thus the opposing effects of Fli-I and FLAP1 may be a key regulatory mechanism for ß-catenin and LEF1/TCF-mediated transcription and thus for Wnt signaling, and some mutations of Fli-I may result in developmental defects, such as the flightless phenotype of Drosophila, by causing dysregulation of the Wnt/ß-catenin pathway.