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J. Biol. Chem., Vol. 278, Issue 40, 38758-38764, October 3, 2003

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The PDZ Protein Tax-interacting Protein-1 Inhibits -Catenin Transcriptional Activity and Growth of Colorectal Cancer Cells^*

Mutsumi Kanamori  , Peter Sandy  ¶ ||, Stefania Marzinotto ¶, Roberta Benetti ¶ **, Chikatoshi Kai , Yoshihide Hayashizaki , Claudio Schneider ¶ and Harukazu Suzuki  

From the Laboratory for Genome Exploration Research Group, RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan, Genome Science Laboratory, RIKEN, 2-1 Hirosawa, Wako 351-0198, Japan, and ^¶Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie, AREA Science Park, Padriciano 99, 34012 Trieste, Italy

Wnt signaling is essential during development while deregulation of this pathway frequently leads to the formation of various tumors including colorectal carcinomas. A key component of the pathway is -catenin that, in association with TCF-4, directly regulates the expression of Wnt-responsive genes. To identify novel binding partners of -catenin that may control its transcriptional activity, we performed a mammalian two-hybrid screen and isolated the Tax-interacting protein (TIP-1). The in vivo complex formation between -catenin and TIP-1 was verified by coimmunoprecipitation, and a direct physical association was revealed by glutathione S-transferase pull-down experiments in vitro. By using a panel of deletion mutants of both proteins, we demonstrate that the interaction is mediated by the PDZ (PSD-95/DLG/ZO-1 homology) domain of TIP-1 and requires primarily the last four amino acids of -catenin. TIP-1 overexpression resulted in a dose-dependent decrease in the transcriptional activity of -catenin when tested on the TOP/FOPFLASH reporter system. Conversely, siRNA-mediated knock-down of endogenous TIP-1 slightly increased endogenous -catenin transactivation function. Moreover, we show that overexpression of TIP-1 reduced the proliferation and anchorage-independent growth of colorectal cancer cells. These data suggest that TIP-1 may represent a novel regulatory element in the Wnt/-catenin signaling pathway.

Received for publication, June 16, 2003 , and in revised form, July 21, 2003.

^* This study has been supported by a research grant for the RIKEN Genome Exploration Research Project from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government (to Y. H.). The work in the laboratory of C. Schneider was supported by an Associazione Italian per la Ricerca sul Cancro grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to the work.

^|| Partially supported by the Hungarian "Eotvos" State fellowship.

^** A Fondazione Italiana per la Ricerca sul Cancro fellow.

To whom correspondence should be addressed. Tel.: 81-45-503-9222; Fax: 81-45-503-9216; E-mail: rgscerg{at}gsc.riken.go.jp.

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