VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400.
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.
Young
Arthur P
AP
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Schlisio
Susanne
S
Minamishima
Yoji Andrew
YA
Zhang
Qing
Q
Li
Lianjie
L
Grisanzio
Chiara
C
Signoretti
Sabina
S
Kaelin
William G
WG
D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D002478:Cells, Cultured; D016922:Cellular Senescence; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D012190:Retroviridae / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism / Q000502:physiology*
D015220:Calcium Channels; D051793:Hypoxia-Inducible Factor 1; D053496:Inositol 1,4,5-Trisphosphate Receptors; C025389:Itpr1 protein, mouse; D008562:Membrane Glycoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D016160:Retinoblastoma Protein; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C494469:VHL protein, mouse; D010100:Oxygen