MCB
Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hu, C.-J.
Right arrow Articles by Simon, M. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hu, C.-J.
Right arrow Articles by Simon, M. C.
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.



This article has been cited by other articles:



Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
J. Bacteriol. J. Virol. Eukaryot. Cell
Microbiol. Mol. Biol. Rev. Clin. Vaccine Immunol. All ASM Journals

Copyright © 2003 by the American Society for Microbiology. All rights reserved.