Cobalt stimulates HIF-1-dependent but inhibits HIF-2-dependent gene expression in liver cancer cells.

Authors:
Christina Befani
Christina Befani
Aristotle University of Thessaloniki
Greece
Ilias Mylonis
Ilias Mylonis
University of Thessaly
Greece
Ioanna-Maria Gkotinakou
Ioanna-Maria Gkotinakou
University of Thessaly
Greece
Panagiotis Georgoulias
Panagiotis Georgoulias
University Hospital of Larissa
Greece
Dr. Cheng-Jun Hu, PhD
Dr. Cheng-Jun Hu, PhD
University of Colorado
Associate Professor
Pulmonary hypertension
Aurora, CO | United States
George Simos
George Simos
University of Thessaly
Greece
Panagiotis Liakos
Panagiotis Liakos
Laboratory of Biochemistry
Madison | United States

Int J Biochem Cell Biol 2013 Nov 16;45(11):2359-68. Epub 2013 Aug 16.

Laboratory of Biochemistry, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Larissa 41110, Greece.

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 HIF-1 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-1α and HIF-2α 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 HIF-1- 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-2α interacted poorly with USF-2, a HIF-2-specific co-activator. These data show that, despite similar induction of HIF-1α and HIF-2α 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.

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Source
http://dx.doi.org/10.1016/j.biocel.2013.07.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3855297PMC
November 2013
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