PML is a target gene of beta-catenin and plakoglobin, and coactivates beta-catenin-mediated transcription.
beta-Catenin and its close homologue plakoglobin (gamma-catenin) are major constituents of submembranal cell-cell adhesion sites. In addition, beta-catenin is a key component in the canonical Wnt pathway. Aberrantly activated beta-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 beta-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 beta-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 beta-catenin. Activation of the PML promoter by beta-catenin and plakoglobin was LEF/TCF-independent. We found that PML forms a complex with beta-catenin in cells, and the two proteins colocalize in the nucleus. In addition, PML, p300, and beta-catenin cooperated in transactivation of a subset of beta-catenin-responsive genes including ARF and Siamois but not cyclin D1. Retroviral expression of beta-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.
Mesh Terms:
Animals, Carcinoma, Renal Cell, Cytoskeletal Proteins, Desmoplakins, Gene Expression Regulation, Neoplastic, Humans, Kidney Neoplasms, Male, Mice, Mice, Nude, Neoplasm Proteins, Neoplasm Transplantation, Nuclear Proteins, Trans-Activators, Transcription Factors, Transcriptional Activation, Transplantation, Heterologous, Tumor Cells, Cultured, Tumor Suppressor Proteins, beta Catenin, gamma Catenin
Animals, Carcinoma, Renal Cell, Cytoskeletal Proteins, Desmoplakins, Gene Expression Regulation, Neoplastic, Humans, Kidney Neoplasms, Male, Mice, Mice, Nude, Neoplasm Proteins, Neoplasm Transplantation, Nuclear Proteins, Trans-Activators, Transcription Factors, Transcriptional Activation, Transplantation, Heterologous, Tumor Cells, Cultured, Tumor Suppressor Proteins, beta Catenin, gamma Catenin
Cancer Res.
Date: Oct. 15, 2002
PubMed ID: 12384561
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