title: Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice.
abstract: The combinations of genetic alterations that cooperate with von Hippel-Lindau (VHL) mutation to cause clear cell renal cell carcinoma (ccRCC) remain poorly understood. We show that the TP53 tumour suppressor gene is mutated in approximately 9% of human ccRCCs. Combined deletion of Vhl and Trp53 in primary mouse embryo fibroblasts causes proliferative dysregulation and high rates of aneuploidy. Deletion of these genes in the epithelium of the kidney induces the formation of simple cysts, atypical cysts and neoplasms, and deletion in the epithelia of the genital urinary tract leads to dysplasia and tumour formation. Kidney cysts display a reduced frequency of primary cilia and atypical cysts and neoplasms exhibit a pro-proliferative signature including activation of mTORC1 and high expression of Myc, mimicking several cellular and molecular alterations seen in human ccRCC and its precursor lesions. As the majority of ccRCC is associated with functional inactivation of VHL, our findings suggest that for a subset of ccRCC, loss of p53 function represents a critical event in tumour development.
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Joachim
authors.initials: J
authors.lastname: Albers
authors.forename: Michal
authors.initials: M
authors.lastname: Rajski
authors.forename: Désirée
authors.initials: D
authors.lastname: Schönenberger
authors.forename: Sabine
authors.initials: S
authors.lastname: Harlander
authors.forename: Peter
authors.initials: P
authors.lastname: Schraml
authors.forename: Adriana
authors.initials: A
authors.lastname: von Teichman
authors.forename: Strahil
authors.initials: S
authors.lastname: Georgiev
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wild
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Krek
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Frew
mesh_terms: D000782:Aneuploidy; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D052177:Kidney Diseases, Cystic / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D019459:Urothelium / Q000166:cytology / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C494469:VHL protein, mouse