International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


POSTER 60 - THE PDZ PROTEIN TIP-1 INHIBITS β-CATENIN TRANSCRIPTIONAL ACTIVITY AND GROWTH OF COLORECTAL CANCER CELLS

Suzuki H
RIKEN GSC

Co-Authors: 1) Kanamori M, 1) Kai C, 1) Hayashizaki Y, 2) Sandy P, 2) Marzinotto S, 2) Benetti R, 2) Schneider C
Institutions: 1) RIKEN GSC, 2) LNCIB

Wnt signaling is indispensable for normal animal development while deregulation of this pathway frequently leads to the formation of various tumors, including colorectal carcinomas. A key molecule of the pathway is β-catenin that, in association with TCF-4, directly regulates the expression of wnt-responsive genes, such as c-myc, PPARδ, matrilysin and cyclin D1. In order to identify novel binding partners of β-catenin that may control its transcriptional activity we performed a mammalian two-hybrid screen and isolated TIP-1. TIP-1 is a small (14 kDa) protein with the PDZ domain and has been first identified in a yeast two-hybrid screen as a Tax interacting protein. The in vivo complex formation between β-catenin and TIP-1 was verified by coimmunoprecipitation and a direct physical association was revealed by GST 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 domain of TIP-1 and requires primarily the last four amino acids of β-catenin with the PDZ-recognition motif (X-S/T-X-V/I/L-COOH). TIP-1 overexpression resulted in a dose-dependent decrease in the transcriptional activity of β-catenin when tested on the reporter system. Further, siRNA-mediated knockdown of endogenous TIP-1 slightly increased endogenous β-catenin transactivation function. Moreover we show that overexpression of TIP-1 reduced the proliferation and anchorage-independent growth of colorectal cancer cells. Thus, these data suggest that TIP-1 may represent a novel regulatory element in the wnt/β-catenin signaling pathway.


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