pVHL acts as a downstream target of E2F1 to suppress E2F1 activity

Abstract

The VHL (von Hippel-Lindau) gene is a well-defined tumour suppressor linked to hereditary cancer syndromes. Although it is well documented that pVHL (von Hippel-Lindau protein) mediates HIF (hypoxia-inducible factor)-1/2α degradation under conditions of normoxia, accounting for a major mechanism of pVHL in tumour suppression, it remains elusive whether other HIF-independent functions contribute to the pVHL tumour suppressive function. In the present study, we found that pVHL is a downstream target of E2F1, which harbours an E2F1-binding site in its promoter. Moreover, pVHL binds to E2F1 in vitro and in vivo, resulting in inhibition of E2F1 transcriptional activity. Mechanistic studies showed that pVHL binding enhances E2F1 deacetylation. Further immunoprecipitation assays indicated that the pVHL interaction diminishes P/CAF [p300/CREB (cAMPresponse-element-binding protein)-binding protein-associated factor] and p300 association with E2F1, but enhances Sirt1 (sirtuin 1) binding to E2F1. In addition, upon DNA damage, pVHL is induced. Knockdown of pVHL sensitizes cells to DNA-damageinduced apoptosis dependent on E2F1, uncovering a role for pVHL in the response to DNA damage. The findings of the present study reveal a novel function of pVHL and demonstrate a negative-feedback loop between pVHL and E2F1, which may shed new light on the explanation of the role of pVHL in tumour suppression.

Oxalomalate reduces expression and secretion of vascular endothelial growth factor in the retinal pigment epithelium and inhibits angiogenesis: Implications for age-related macular degeneration

“…However, this data did not provide insight into the nature of this association. We considered the E2F1 transcription factor as a potential candidate to establish a link between pVHL activity and OMA because pVHL is a direct downstream target of E2F1 [63]. In addition, recently it was reported that the phosphorylated and active form of E2F1 is regulated in ROS-dependent manner [64], [65].…”

Suppression of homology-dependent DNA double-strand break repair induces PARP inhibitor sensitivity inVHL-deficient human renal cell carcinoma

“…Although a role for VHL in DNA repair has not been studied as intensely as its role in angiogenesis and promotion of tumor growth, there have been several studies that support a connection between VHL and DNA repair. First, the VHL isoform pVHL 19 has been found to localize to the nucleus and to be up-regulated in response to DNA damage [ 63 , 64 ]. pVHL has also been shown to localize to the mitotic spindle and prevent misorientation of the spindle during mitosis [ 45 ].…”

The multifaceted von Hippel–Lindau tumour suppressor protein

“…al. reported a feedback loop wherein pVHL regulates E2F1 activity which in turn regulates pVHL expression [36]. Recently, a possible physiologic role for pVHL in the DNA damage response was revealed whereby suppressor of cytokine signalling 1 (SOCS1) mediates the nuclear redistribution and ubiquitylation of pVHL upon induction of double-stranded DNA breaks.…”