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.
Shtutman
Michael
M
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Zhurinsky
Jacob
J
Oren
Moshe
M
Levina
Elina
E
Ben-Ze'ev
Avri
A
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000502:physiology*; D051180:Desmoplakins; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D051185:gamma Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D051180:Desmoplakins; C495292:JUP protein, human; C495293:Jup protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D051185:gamma Catenin; C070576:PML protein, human