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VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400

Nature Cell Biology volume 10, pages 361–369 (2008)Cite this article

Abstract

Germline von Hippel–Lindau tumour suppressor gene (VHL) mutations cause renal cell carcinomas, haemangioblastomas and phaeochromocytomas in humans1. Mutations in VHL also occur in sporadic renal cell carcinomas. The protein encoded by VHL, VHL, is part of the ubiquitin ligase that downregulates the heterodimeric transcription factor Hif under well-oxygenated conditions1. Here we show that acute VHL inactivation causes a senescent-like phenotype in vitro and in vivo. This phenotype was independent of p53 and Hif but dependent on the retinoblastoma protein (Rb) and the SWI2/SNF2 chromatin remodeller p400. Rb activation occurred through a decrease in Skp2 messenger RNA, which resulted in the upregulation of p27 in a Hif-independent fashion. Our results suggest that senescence induced by VHL inactivation is a tumour-suppressive mechanism that must be overcome to develop VHL-associated neoplasias.

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Figure 1: Acute loss of VHL induces a senescence-like phenotype.
Figure 2: Senescence due to VHL loss is independent of Hif.
Figure 3: Senescence due to loss of VHL is dependent on Rb, p27 and Skp2.
Figure 4: Senescence due to VHL inactivation linked to p400 loss.
Figure 5: Senescence due to VHL loss occurs in vivo.

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Acknowledgements

This work was supported by the National Institutes of Health, HHMI, Doris Duke Foundation and the Murray Foundation.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Arthur P. Young, Susanne Schlisio, Yoji Andrew Minamishima, Qing Zhang, Lianjie Li & William G. Kaelin Jr

  2. Department of Pathology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Chiara Grisanzio & Sabina Signoretti

  3. Howard Hughes Medical Institute, Chevy Chase, 20815, Maryland, USA

    Lianjie Li & William G. Kaelin Jr

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Contributions

A. P. Y. and S. Schlisio designed the experiments; A. P. Y., S. Schlisio, Y. A. M., Q. Z., L. L. and C. G. performed the experiments; S. Signoretti analysed the data; A. P. Y. and W. G. K. analysed the data and wrote the paper.

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Correspondence to William G. Kaelin Jr.

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Supplementary figures S1, S2, S3, S4, S5 and S6 (PDF 2345 kb)

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Young, A., Schlisio, S., Minamishima, Y. et al. VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. Nat Cell Biol 10, 361–369 (2008). https://doi.org/10.1038/ncb1699

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