WT1 induces apoptosis through transcriptional regulation of the proapoptotic Bcl-2 family member Bak.
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.
Morrison
Debra J
DJ
Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
English
Milton A
MA
Licht
Jonathan D
JD
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
C494772:BAK1 protein, human; C494773:Bak1 protein, mouse; D004273:DNA, Neoplasm; D025721:WT1 Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein