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

Arthur P. Young, Susane Schisio, Yoji Andrews Minamishima, Qing Zhang, Lianjie Li, Chiara Grisanzio, Sabina Signoretti, William G. Kaelin

Research output: Contribution to journalArticle

173 Citations (Scopus)

Abstract

Germline von Hippel-Lindau tumour suppressor gene (VHL) mutations cause renal cell carcinomas, haemangioblastomas and phaeochromocytomas in humans. 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 conditions. 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.

Original languageEnglish (US)
Pages (from-to)361-369
Number of pages9
JournalNature Cell Biology
Volume10
Issue number3
DOIs
StatePublished - Mar 1 2008
Externally publishedYes

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Renal Cell Carcinoma
Hemangioblastoma
Phenotype
Retinoblastoma Protein
Mutation
Pheochromocytoma
Ligases
Ubiquitin
Tumor Suppressor Genes
Chromatin
Neoplasms
Transcription Factors
Up-Regulation
Down-Regulation
Messenger RNA
Proteins
In Vitro Techniques

ASJC Scopus subject areas

  • Cell Biology

Cite this

Young, A. P., Schisio, S., Minamishima, Y. A., Zhang, Q., Li, L., Grisanzio, C., ... Kaelin, W. G. (2008). VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. Nature Cell Biology, 10(3), 361-369. https://doi.org/10.1038/ncb1699

VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. / Young, Arthur P.; Schisio, Susane; Minamishima, Yoji Andrews; Zhang, Qing; Li, Lianjie; Grisanzio, Chiara; Signoretti, Sabina; Kaelin, William G.

In: Nature Cell Biology, Vol. 10, No. 3, 01.03.2008, p. 361-369.

Research output: Contribution to journalArticle

Young, AP, Schisio, S, Minamishima, YA, Zhang, Q, Li, L, Grisanzio, C, Signoretti, S & Kaelin, WG 2008, 'VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400', Nature Cell Biology, vol. 10, no. 3, pp. 361-369. https://doi.org/10.1038/ncb1699
Young, Arthur P. ; Schisio, Susane ; Minamishima, Yoji Andrews ; Zhang, Qing ; Li, Lianjie ; Grisanzio, Chiara ; Signoretti, Sabina ; Kaelin, William G. / VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. In: Nature Cell Biology. 2008 ; Vol. 10, No. 3. pp. 361-369.
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