Letter abstract

Nature Cell Biology 10, 361 - 369 (2008)
Published online: 24 February 2008 | doi:10.1038/ncb1699

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

Arthur P. Young1, Susanne Schlisio1, Yoji Andrew Minamishima1, Qing Zhang1, Lianjie Li1,3, Chiara Grisanzio2, Sabina Signoretti2 & William G. Kaelin, Jr1,3

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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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  1. Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
  2. Department of Pathology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
  3. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.

Correspondence to: William G. Kaelin, Jr1,3 e-mail: william_kaelin@dfci.harvard.edu



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