Target Gene Activation by PCatenin

Once in the nucleus, P-catenin forms a stable complex with Tcf/Lef family transcription factors to stimulate gene expression (Stadeli et al. 2006; Willert and Jones 2006). The vertebrate genome encodes four Tcf/Lef proteins (Tcfl, Tcf3, Tcf4 and Lef1), which contain the highly conserved high-mobility group (HMG) box as a DNA-binding domain (Arce et al. 2006; Hoppler and Kavanagh 2007). In the absence of nuclear P-catenin, Tcf/Lef factors are bound to the co-repressors Gro/TLE and CtBP, actively suppressing target gene transcription. Both Gro/TLE and CtBP interact with histone deacetylases in order to silence transcription by altering local chromatin structure (Courey and Jia 2001).

P-Catenin binds to Tcf/Lef by displacing Gro/TLE (Daniels and Weis 2005). This allows P-catenin to recruit a variety of co-activators necessary to exert its transcriptional potential. Earlier studies have demonstrated that P-catenin harbors two transactivation domains, N-terminal activation domain (NTAD) and C-terminal activation domain (CTAD) (Hecht et al. 1999; Hsu et al. 1998; van de Wetering et al. 1997) (Fig. 2). Each of these domains on its own potently stimulates gene expression. In particular, the CTAD alone has been shown to be sufficient both for signaling and for oncogenic transformation (Aoki et al. 1999; Vleminckx et al. 1999).

A considerable number of direct target genes of the Tcf/P-catenin complex has been identified in various model systems, including c-Myc (He et al. 1998), cyclin D1 (Tetsu and McCormick 1999), MMP7 (matrilysin) (Crawford et al. 1999) and Nr-CAM (Conacci-Sorrell et al. 2002). For a comprehensive list of Wnt target genes, we direct the readers to the Wnt Homepage (http://www.stanford.edu/~rnusse/ wntwindow.html). Also worthy of note, P-catenin modulates expression of several components of the Wnt pathway, such as an Axin homolog Axin2 (conductin) (Jho et al. 2002; Lustig et al. 2002), pTrCP (Spiegelman et al. 2000) and Tcf/Lef (Hovanes et al. 2001; Roose et al. 1999), thereby creating a negative or positive feedback loop. Generally, cellular responses to Wnt signals vary among different cell types, and many Wnt target genes are, in fact, regulated in a cell-type-specific fashion.

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