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Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis
Journal article   Open access   Peer reviewed

Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis

Shan-Shan Wang, Yi-Feng Gu, Nicholas Wolff, Karoliina Stefanius, Alana Christie, Anwesha Dey, Robert E Hammer, Xian-Jin Xie, Dinesh Rakheja, Ivan Pedrosa, …
Proceedings of the National Academy of Sciences - PNAS, Vol.111(46), pp.16538-16543
11/18/2014
DOI: 10.1073/pnas.1414789111
PMCID: PMC4246264
PMID: 25359211
url
https://doi.org/10.1073/pnas.1414789111View
Published (Version of record) Open Access

Abstract

Why different species are predisposed to different tumor spectra is not well understood. In particular, whether the physical location of tumor suppressor genes relative to one another influences tumor predisposition is unknown. Renal cancer presents a unique opportunity to explore this question. Renal cell carcinoma (RCC) of clear-cell type (ccRCC), the most common type, begins with an intragenic mutation in the von Hippel-Lindau (VHL) gene and loss of 3p (where VHL is located). Chromosome 3p harbors several additional tumor suppressor genes, including BRCA1-associated protein-1 (BAP1). In the mouse, Vhl is on a different chromosome than Bap1. Thus, whereas loss of 3p in humans simultaneously deletes one copy of BAP1, loss of heterozygosity in the corresponding Vhl region in the mouse would not affect Bap1. To test the role of BAP1 in ccRCC development, we generated mice deficient for either Vhl or Vhl together with one allele of Bap1 in nephron progenitor cells. Six2-Cre;Vhl(F/F);Bap1(F/+) mice developed ccRCC, but Six2-Cre;Vhl(F/F) mice did not. Kidneys from Six2-Cre;Vhl(F/F);Bap1(F/+) mice resembled kidneys from humans with VHL syndrome, containing multiple lesions spanning from benign cysts to cystic and solid RCC. Although the tumors were small, they showed nuclear atypia and exhibited features of human ccRCC. These results provide an explanation for why VHL heterozygous humans, but not mice, develop ccRCC. They also explain why a mouse model of ccRCC has been lacking. More broadly, our data suggest that differences in tumor predisposition across species may be explained, at least in part, by differences in the location of two-hit tumor suppressor genes across the genome.
 Mutation Phenotype Kidney Neoplasms - genetics Species Specificity Tumor Suppressor Proteins - antagonists & inhibitors Humans Multipotent Stem Cells - metabolism Carcinoma, Renal Cell - genetics Male Kidney Failure, Chronic - pathology Tumor Suppressor Proteins - genetics Kidney Diseases, Cystic - genetics Female Precancerous Conditions - pathology Von Hippel-Lindau Tumor Suppressor Protein - genetics Von Hippel-Lindau Tumor Suppressor Protein - antagonists & inhibitors Genes, Tumor Suppressor Ubiquitin Thiolesterase - antagonists & inhibitors Genes, Reporter Disease Models, Animal Genetic Predisposition to Disease Mice, Inbred C57BL Genes, Synthetic Von Hippel-Lindau Tumor Suppressor Protein - physiology Mice, Transgenic Chromosome Mapping Ubiquitin Thiolesterase - physiology Ubiquitin Thiolesterase - genetics Precancerous Conditions - genetics Kidney Diseases, Cystic - pathology Mice, Knockout Kidney Failure, Chronic - genetics Cell Lineage Tumor Suppressor Proteins - physiology Multipotent Stem Cells - pathology Animals Kidney Failure, Chronic - blood Age of Onset Alleles Mice Models, Genetic

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