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Molecular and Cellular Biology, November 2007, p. 7560-7573, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00315-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

PITX2 and ß-Catenin Interactions Regulate Lef-1 Isoform Expression{triangledown}

Melanie Amen,1 Xiaoming Liu,2 Usha Vadlamudi,3 Gabriela Elizondo,4 Evan Diamond,1 John F. Engelhardt,2 and Brad A. Amendt1*

Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas,1 Department of Anatomy and Cell Biology, University of Iowa College of Medicine, Iowa City, Iowa,2 Department of Biological Science, The University of Tulsa, Tulsa, Oklahoma,3 Escuela de Medicina, Tecnologico De Monterrey, Monterrey, Mexico4

Received 21 February 2007/ Returned for modification 9 May 2007/ Accepted 20 August 2007

Lef-1 and PITX2 function in the Wnt signaling pathway by recruiting and interacting with ß-catenin to activate target genes. Chromatin immunoprecipitation (ChIP) assays identified the Lef-1 promoter as a PITX2 downstream target. Transgenic mice expressing LacZ driven by the 2.5-kb LEF-1 promoter demonstrated expression in the tooth epithelium correlated with endogenous Lef-1 FL epithelial expression. PITX2 isoforms regulate the LEF-1 promoter, and ß-catenin synergistically enhanced activation of the LEF-1 promoter in combination with PITX2 and Lef-1 isoforms. PITX2 enhances endogenous expression of the full-length ß-catenin-dependent Lef-1 isoform (Lef-1 FL) while decreasing expression of the N-terminally truncated ß-catenin-independent isoform. Our research revealed a novel interaction between PITX2, Lef-1, and ß-catenin in which the Lef-1 ß-catenin binding domain is dispensable for its interaction with PITX2. PITX2 interacts with two sites within the Lef-1 protein. Furthermore, ß-catenin interacts with the PITX2 homeodomain and Lef-1 interacts with the PITX2 C-terminal tail. Lef-1 and ß-catenin interact simultaneously and independently with PITX2 through two different sites to regulate PITX2 transcriptional activity. These data support a role for PITX2 in cell proliferation, migration, and cell division through differential Lef-1 isoform expression and interactions with Lef-1 and ß-catenin.

* Corresponding author. Mailing address: Texas A&M Health Science Center, Institute of Biosciences and Genetic Medicine, 2121 W. Holcombe Boulevard, Houston, TX 77030. Phone: (713) 677-7402. Fax: (713) 677-7784. E-mail: bamendt{at}ibt.tamhsc.edu

{triangledown} Published ahead of print on 4 September 2007.

Molecular and Cellular Biology, November 2007, p. 7560-7573, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00315-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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