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 HIP (hypoxia-inducible factor)-1/2 alpha degradation under conditions of normoxia, accounting for a major mechanism of pVHL in tumour suppression, it remains elusive whether other HIP-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 (cAMP-response-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-damage-induced 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.
英文摘要:
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 HIP (hypoxia-inducible factor)-1/2 alpha degradation under conditions of normoxia, accounting for a major mechanism of pVHL in tumour suppression, it remains elusive whether other HIP-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 (cAMP-response-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-damage-induced 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.
1.Chinese Acad Sci, Inst Hydrobiol, Key Lab Aquat Biodivers & Conservat, Wuhan 430072, Peoples R China 2.Huazhong Agr Univ, Coll Fisheries, Dept Aquat Anim Med, Wuhan 430070, Peoples R China
Recommended Citation:
Ji, Wei; Wang, Jing; Zhang, Wei; Liu, Xing; Ouyang, Gang; Xiao, Wuhan.pVHL acts as a downstream target of E2F1 to suppress E2F1 activity,BIOCHEMICAL JOURNAL,2014,457():185-195
