title: WT1 induces apoptosis through transcriptional regulation of the proapoptotic Bcl-2 family member Bak.
abstract: 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.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Morrison
authors.forename: Milton A
authors.initials: MA
authors.lastname: English
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Licht
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000096:biosynthesis; D016162:Genes, Wilms Tumor; D006801:Humans; D051379:Mice; D020125:Mutation, Missense; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation; D025721:WT1 Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C494772:BAK1 protein, human; C494773:Bak1 protein, mouse; D004273:DNA, Neoplasm; D025721:WT1 Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein