These authors contributed equally to this work.
Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice
Article first published online: 22 APR 2013
Copyright © 2013 EMBO Molecular Medicine
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 5, Issue 6, pages 949–964, June 2013
How to Cite
Albers, J., Rajski, M., Schönenberger, D., Harlander, S., Schraml, P., von Teichman, A., Georgiev, S., Wild, P. J., Moch, H., Krek, W. and Frew, I. J. (2013), Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice. EMBO Mol Med, 5: 949–964. doi: 10.1002/emmm.201202231
- Issue published online: 4 JUN 2013
- Article first published online: 22 APR 2013
- Manuscript Accepted: 12 MAR 2013
- Manuscript Revised: 8 MAR 2013
- Manuscript Received: 2 NOV 2012
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.