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Molecular Biology, Pathobiology and Genetics |
1 Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York and 2 National Human Genome Research Institute, Bethesda, Maryland
Requests for reprints: Jonathan D. Licht, Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, Box 1079, One Gustave L. Levy Place, New York, NY 10029. Phone: 212-241-8220; Fax: 212-849-2523; E-mail: jonathan.licht{at}mssm.edu.
Wilms' tumor or nephroblastoma is believed to arise from embryonic nephrogenic rests of multipotent cells that fail to terminally differentiate into epithelium and continue to proliferate. The WT1 tumor suppressor gene, a transcription factor controlling the mesenchymal-epithelial transition in renal development, is mutated in 10% to 15% of Wilms' tumors. This potentially explains the disordered differentiation and proliferation program of a subset of Wilms' tumors. To elucidate the role of mutations of WT1 in the etiology of Wilms' tumor, we used an inducible cellular system for expressing wild-type and tumor-derived missense mutant WT1 proteins. Expression of wild-type WT1, but not mutant proteins, blocked cellular proliferation and DNA synthesis and rapidly induced apoptosis. We showed that wild-type WT1 induced transcription of one of the seven studied proapoptotic genes, Bak. Furthermore, WT1 protein bound to specific DNA-binding sites located in the Bak promoter and Bak was critical to WT1-mediated apoptosis, as overexpression of VDAC2, a specific Bak inhibitor, attenuated WT1-mediated cell death. These data support the hypothesis that Wilms' tumors arise, in part, because WT1 mutant proteins fail to promote programmed cell death during kidney development.
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