VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400
Copyright policy )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.
- Harvard University United States
- Brigham and Women's Faulkner Hospital United States
- Michigan Medicine United States
- Dana-Farber Cancer Institute United States
- Howard Hughes Medical Institute United States
Membrane Glycoproteins, Receptors, Cytoplasmic and Nuclear, Mice, Transgenic, Fibroblasts, Retinoblastoma Protein, Oxygen, Mice, Phenotype, Retroviridae, Gene Expression Regulation, Von Hippel-Lindau Tumor Suppressor Protein, Mutation, Animals, Inositol 1,4,5-Trisphosphate Receptors, Calcium Channels, Hypoxia-Inducible Factor 1, Cells, Cultured, Cellular Senescence
Membrane Glycoproteins, Receptors, Cytoplasmic and Nuclear, Mice, Transgenic, Fibroblasts, Retinoblastoma Protein, Oxygen, Mice, Phenotype, Retroviridae, Gene Expression Regulation, Von Hippel-Lindau Tumor Suppressor Protein, Mutation, Animals, Inositol 1,4,5-Trisphosphate Receptors, Calcium Channels, Hypoxia-Inducible Factor 1, Cells, Cultured, Cellular Senescence
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