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Molecular and Cellular Biology, August 2006, p. 5827-5837, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.00441-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Functional Interaction between Peroxisome Proliferator-Activated Receptor {gamma} and ß-Catenin{dagger}

Jiajian Liu, Hong Wang, Ying Zuo, and Stephen R. Farmer*

Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118

Received 13 March 2006/ Returned for modification 7 April 2006/ Accepted 16 May 2006

Studies have demonstrated cross talk between ß-catenin and peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) signaling pathways. Specifically, activation of PPAR{gamma} induces the proteasomal degradation of ß-catenin in cells that express an adenomatous polyposis coli-containing destruction complex. In contrast, oncogenic ß-catenin is resistant to such degradation and inhibits the expression of PPAR{gamma} target genes. In the present studies, we demonstrate a functional interaction between ß-catenin and PPAR{gamma} that involves the T-cell factor (TCF)/lymphocyte enhancer factor (LEF) binding domain of ß-catenin and a catenin binding domain (CBD) within PPAR{gamma}. Mutation of K312 and K435 in the TCF/LEF binding domain of an oncogenic ß-catenin (S37A) significantly reduces its ability to interact with and inhibit the activity of PPAR{gamma}. Furthermore, these mutations render S37A ß-catenin susceptible to proteasomal degradation in response to activation of PPAR{gamma}. Mutation of F372 within the CBD (helices 7 and 8) of PPAR{gamma} disrupts its binding to ß-catenin and significantly reduces the ability of PPAR{gamma} to induce the proteasomal degradation of ß-catenin. We suggest that in normal cells, PPAR{gamma} can function to suppress tumorigenesis and/or Wnt signaling by targeting phosphorylated ß-catenin to the proteasome through a process involving its CBD. In contrast, oncogenic ß-catenin resists proteasomal degradation by inhibiting PPAR{gamma} activity, which requires its TCF/LEF binding domain.

* Corresponding author. Mailing address: Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118. Phone: (617) 638-4186. Fax: (617) 638-5339. E-mail: farmer{at}biochem.bumc.bu.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2006, p. 5827-5837, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.00441-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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