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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Acknowledgements
This work was supported by the National Institutes of Health, HHMI, Doris Duke Foundation and the Murray Foundation.
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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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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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DOI: https://doi.org/10.1038/ncb1699
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