Open AccessCombined mutation of Vhl and Trp53 causes renal cysts and tumours in mice
Author(s) -
Albers Joachim,
Rajski Michal,
Schönenberger Désirée,
Harlander Sabine,
Schraml Peter,
von Teichman Adriana,
Georgiev Strahil,
Wild Peter J.,
Moch Holger,
Krek Wilhelm,
Frew Ian J.
Publication year - 2013
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201202231
Subject(s) - biology , cancer research , clear cell renal cell carcinoma , pathology , mutation , dysplasia , clear cell , aneuploidy , kidney , ciliogenesis , cilium , renal cell carcinoma , gene , carcinoma , chromosome , medicine , genetics
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.