PML Is a Target Gene of -Catenin and Plakoglobin, and Coactivates -Catenin-mediated Transcription

-Catenin and its close homologue plakoglobin ( -catenin) are major constituents of submembranal cell-cell adhesion sites. In addition, -catenin is a key component in the canonical Wnt pathway. Aberrantly activated -catenin signaling contributes to cancer progression by inducing [in complex with lymphocyte enhancer factor (LEF)/T-cell factor (TCF)] the transcription of proliferation-related genes such as cyclin D1 and c-myc. Plakoglobin can also activate LEF/TCF-mediated transcription. Excessive -catenin signaling in MEF triggers a p53-mediated antiproliferative response by inducing the expression of ARF. We have demonstrated previously that plakoglobin also exerts a tumor-suppressive effect in certain cancer cell lines. To identify genes induced by -catenin and plakoglobin, DNA microarray analysis was carried out, and PML was among those genes of which the expression was significantly elevated by both plakoglobin and -catenin. Activation of the PML promoter by -catenin and plakoglobin was LEF/TCF-independent. We found that PML forms a complex with -catenin in cells, and the two proteins colocalize in the nucleus. In addition, PML, p300, and -catenin cooperated in transactivation of a subset of -catenin-responsive genes including ARF and Siamois but not cyclin D1. Retroviral expression of -catenin, plakoglobin, or PML suppressed the tumorigenicity of p53-negative human renal carcinoma cells, thus pointing to a novel antioncogenic response triggered by catenins that is mediated by the induction of PML.