Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis
Abstract
Despite the discovery of the von Hippel-Lindau (VHL) gene in 1993, and that inactivating germ-line mutations of VHL cause multiple kidney lesions, including clear-cell renal cell carcinoma (ccRCC), Vhl inactivation in the mouse does not lead to ccRCC and a mouse model has been lacking. We discovered that the BRCA1-associated protein-1 (BAP1) two-hit tumor suppressor gene is mutated in ccRCC, and one BAP1 allele is frequently somatically codeleted with VHL in tumors. In the mouse, Vhl and Bap1 are on different chromosomes. We show that SIX homeobox 2 (Six2)-Cre;VhlF/F;Bap1F/+ mice develop premalignant lesions and malignant ccRCC resembling VHL syndrome. More broadly, differences in tumor predisposition across species may result from differences in the location of two-hit tumor suppressor genes across the genome.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- November 2014
- DOI:
- 10.1073/pnas.1414789111
- Bibcode:
- 2014PNAS..11116538W