Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice

Authors

  • Joachim Albers,

    1. Institute of Physiology, University of Zurich, Zurich, Switzerland
    2. Competence Center for Systems Physiology and Metabolic Diseases, ETH Zurich and University of Zurich, Zurich, Switzerland
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    • These authors contributed equally to this work.

  • Michal Rajski,

    1. Institute of Physiology, University of Zurich, Zurich, Switzerland
    2. Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
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    • These authors contributed equally to this work.

  • Désirée Schönenberger,

    1. Institute of Physiology, University of Zurich, Zurich, Switzerland
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    • These authors contributed equally to this work.

  • Sabine Harlander,

    1. Institute of Physiology, University of Zurich, Zurich, Switzerland
    2. Competence Center for Systems Physiology and Metabolic Diseases, ETH Zurich and University of Zurich, Zurich, Switzerland
    3. Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
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    • These authors contributed equally to this work.

  • Peter Schraml,

    1. Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland
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  • Adriana von Teichman,

    1. Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland
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  • Strahil Georgiev,

    1. Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
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  • Peter J. Wild,

    1. Competence Center for Systems Physiology and Metabolic Diseases, ETH Zurich and University of Zurich, Zurich, Switzerland
    2. Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland
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  • Holger Moch,

    1. Competence Center for Systems Physiology and Metabolic Diseases, ETH Zurich and University of Zurich, Zurich, Switzerland
    2. Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland
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  • Wilhelm Krek,

    1. Competence Center for Systems Physiology and Metabolic Diseases, ETH Zurich and University of Zurich, Zurich, Switzerland
    2. Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
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  • Ian J. Frew

    Corresponding author
    1. Institute of Physiology, University of Zurich, Zurich, Switzerland
    2. Competence Center for Systems Physiology and Metabolic Diseases, ETH Zurich and University of Zurich, Zurich, Switzerland
    3. Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
    • Tel: +41 44 635 5004; Fax: +41 44 635 6814

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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.

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