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Molecular and Cellular Biology, December 2003, p. 9361-9374, Vol. 23, No. 24
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.24.9361-9374.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Differential Roles of Hypoxia-Inducible Factor 1{alpha} (HIF-1{alpha}) and HIF-2{alpha} in Hypoxic Gene Regulation

Cheng-Jun Hu,1 Li-Yi Wang,2 Lewis A. Chodosh,1 Brian Keith,1 and M. Celeste Simon1,2*

Abramson Family Cancer Research Institute,1 Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 191042

Received 7 March 2003/ Returned for modification 24 April 2003/ Accepted 4 September 2003

Transcriptional responses to hypoxia are primarily mediated by hypoxia-inducible factor (HIF), a heterodimer of HIF-{alpha} and the aryl hydrocarbon receptor nuclear translocator subunits. The HIF-1{alpha} and HIF-2{alpha} subunits are structurally similar in their DNA binding and dimerization domains but differ in their transactivation domains, implying they may have unique target genes. Previous studies using Hif-1{alpha}-/- embryonic stem and mouse embryonic fibroblast cells show that loss of HIF-1{alpha} eliminates all oxygen-regulated transcriptional responses analyzed, suggesting that HIF-2{alpha} is dispensable for hypoxic gene regulation. In contrast, HIF-2{alpha} has been shown to regulate some hypoxia-inducible genes in transient transfection assays and during embryonic development in the lung and other tissues. To address this discrepancy, and to identify specific HIF-2{alpha} target genes, we used DNA microarray analysis to evaluate hypoxic gene induction in cells expressing HIF-2{alpha} but not HIF-1{alpha}. In addition, we engineered HEK293 cells to express stabilized forms of HIF-1{alpha} or HIF-2{alpha} via a tetracycline-regulated promoter. In this first comparative study of HIF-1{alpha} and HIF-2{alpha} target genes, we demonstrate that HIF-2{alpha} does regulate a variety of broadly expressed hypoxia-inducible genes, suggesting that its function is not restricted, as initially thought, to endothelial cell-specific gene expression. Importantly, HIF-1{alpha} (and not HIF-2{alpha}) stimulates glycolytic gene expression in both types of cells, clearly showing for the first time that HIF-1{alpha} and HIF-2{alpha} have unique targets.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 421 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 746-5532. Fax: (215) 746-5511. E-mail: celeste2{at}mail.med.upenn.edu.

Molecular and Cellular Biology, December 2003, p. 9361-9374, Vol. 23, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.24.9361-9374.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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