Abstract
The role of the hypoxia-inducible factor (HIF) subunits 1α and 2α in response to hypoxia is well established in lung epithelial cells, whereas little is known about HIF-3α with respect to transcriptional and translational regulation by hypoxia. HIF-3α and HIF-1α are two similar but distinct basic helix-loop-helix-PAS proteins, which have been postulated to activate hypoxia responsive genes in response to hypoxia. Here, we used quantitative real time RT-PCR and immunoblotting to determine the activation of HIF-3α vs. HIF-1α by hypoxia. HIF-3α was strongly induced by hypoxia (1% O2) both at the level of protein and mRNA due to an increase in protein stability and transcriptional activation, whereas HIF-1α protein and mRNA levels enhanced transiently and then decreased because of a reduction in its mRNA stability in A549 cells, as measured on mRNA and protein levels. Interestingly, HIF-3α and HIF-1α exhibited strikingly similar responses to a variety of activating or inhibitory pharmacological agents. These results demonstrate that HIF-3α is expressed abundantly in lung epithelial cells, and that the transcriptional induction of HIF-3α plays an important role in the response to hypoxia in vitro. Our findings suggest that HIF-3α, as a member of the HIF system, is complementary rather than redundant to HIF-1α induction in protection against hypoxic damage in alveolar epithelial cells.
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The authors are extremely grateful to Prof Jing-yuan Fang of Shanghai Institute of Digestive Disease for excellent technical assistance.
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Li, Q., Wang, X., Yang, Y. et al. Hypoxia upregulates hypoxia inducible factor (HIF)-3α expression in lung epithelial cells: characterization and comparison with HIF-1α. Cell Res 16, 548–558 (2006). https://doi.org/10.1038/sj.cr.7310072
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DOI: https://doi.org/10.1038/sj.cr.7310072
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