Cobalt stimulates HIF-1-dependent but inhibits HIF-2-dependent gene expression in liver cancer cells
Author
Befani, C.; Mylonis, I.; Gkotinakou, I. M.; Georgoulias, P.; Hu, C. J.; Simos, G.; Liakos, P.Date
2013Keyword
Abstract
Hypoxia-inducible factors (HIFs) are transcriptional regulators that mediate the cellular response to low oxygen. Although HIF-1 is usually considered as the principal mediator of hypoxic adaptation, several tissues and different cell types express both HIF-1 and HIF-2 isoforms under hypoxia or when treated with hypoxia mimetic chemicals such as cobalt. However, the similarities or differences between HIFI and HIF-2, in terms of their tissue- and inducer-specific activation and function, are not adequately characterized. To address this issue, we investigated the effects of true hypoxia and hypoxia mimetics on HIF-1 and HIF-2 induction and specific gene transcriptional activity in two hepatic cancer cell lines, Huh7 and HepG2. Both hypoxia and cobalt caused rapid induction of both HIF-l alpha and HIF-2 alpha proteins. Hypoxia induced erythropoietin (EPO) expression and secretion in a HIF-2-dependent way. Surprisingly, however, EPO expression was not induced when cells were treated with cobalt. In agreement, both HIFI - and HIF-2-dependent promoters (of PGK and SOD2 genes, respectively) were activated by hypoxia while cobalt only activated the HIF-1-dependent PGK promoter. Unlike cobalt, other hypoxia mimetics such as DFO and DMOG activated both types of promoters. Furthermore, cobalt impaired the hypoxic stimulation of HIF-2, but not HIF-1, activity and cobalt-induced HIF-2a interacted poorly with USF-2, a HIF-2-specific co-activator. These data show that, despite similar induction of HIF-la and HIF-2a protein expression, HIF-1 and HIF-2 specific gene activating functions respond differently to different stimuli and suggest the operation of oxygen-independent and gene- or tissue-specific regulatory mechanisms involving additional transcription factors or co-activators. (C) 2013 Elsevier Ltd. All rights reserved.
Collections
Related items
Showing items related by title, author, creator and subject.
-
Hypoxia upregulates integrin gene expression in microvascular endothelial cells and promotes their migration and capillary-like tube formation
Befani C., Liakos P. (2017)Tissue hypoxia affects gene expression through the hypoxia-inducible transcription factors, HIF-1 and HIF-2, in both physiological and pathological angiogenesis. Angiogenesis is a complex response of endothelial cells ... -
Reoxygenation induces reactive oxygen species production and ferroptosis in renal tubular epithelial cells by activating aryl hydrocarbon receptor
Eleftheriadis T., Pissas G., Filippidis G., Liakopoulos V., Stefanidis I. (2021)During the reperfusion phase of ischemia‑reper‑ fusion injury, reactive oxygen species (ROS) production aggravates the course of many diseases, including acute kidney injury. Among the various enzymes implicated in ROS ... -
Association of anti-CCP positivity and carriage of TNFRII susceptibility variant with anti-TNF-α response in rheumatoid arthritis
Vasilopoulos, Y.; Bagiatis, V.; Stamatopoulou, D.; Zisopoulos, D.; Alexiou, I.; Sarafidou, T.; Settas, L.; Sakkas, L.; Mamuris, Z. (2011)Objective: To investigate the possible influence of tumour necrosis factoralpha (TNF), TNF receptor I (TNFRI) and TNF receptor II (TNFRII) gene polymorphisms on anti-TNF treatment responsiveness, stratified by autoantibody ...