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.

Rta, mainly encoded by open reading frame 50 (ORF50), is the product of an immediate-early gene of human herpesvirus-8 (HHV-8)/Kaposi's sarcoma-associated herpesvirus. Rta is a transcriptional activator that is both necessary and sufficient to disrupt viral latency and activate the expression of downstream viral lytic genes. We report that ectopically expressed Rta protein could also activate the rta promoter on a reporter plasmid up to 144-fold, both in latently infected B cells and in uninfected epithelial cells, and that this activation was dose-dependent. Furthermore, by analysing the 5h untranslated region using ribonuclease protection assays, we demonstrated that transfection of an Rta expression plasmid into latently infected cells activated the expression of rta transcripts from endogenous viral genomes. We propose that autoactivation of the immediate-early gene, rta, is an important strategy for HHV-8 to effectively respond to environmental stimuli and maximally activate the virus lytic cycle.