ORIGINAL ARTICLE

Cell Research (2006)16:548-558
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Hypoxia upregulates hypoxia inducible factor (HIF)-3α expression in lung epithelial cells: characterization and comparison with HIF-1α

Qi Fang Li, Xiang Rui Wang, Yue Wu Yang, Han Lin

¹Department of Anesthesiology, Renji Hospital, Shanghai Second Medical University, 1630 Dongfang Road, Shanghai 200127, China

Correspondence: Xiang Rui Wang Tel: 86-21-50903239; Fax: 86-21-50903239 E-mail: xiangruiwang@yahoo.com.cn Received 31 Aug 2005; revised 22 Mar 2006; accepted 4 Apr 2006; published online 15 Jun 2006

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The role of the hypoxia-inducible factor (HIF) subunits 1a and 2a 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.

Cell Research (2006) 16:548-558. doi:10.1038/sj.cr.7310072; published online 15 June 2006

Keywords: hypoxia inducible factor, alveolar epithelial type II cells, hypoxia, gene expression, in vitro