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Vol. 18, Issue 11, 4528-4542, November 2007
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and HIF-2
*Abramson Family Cancer Research Institute and Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and Department of Craniofacial Biology, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045
Submitted May 15, 2006;
Revised August 14, 2007;
Accepted August 27, 2007
Monitoring Editor: William Tansey
The basic helix-loop-helix-Per-ARNT-Sim–proteins hypoxia-inducible factor (HIF)-1
and HIF-2 are the principal regulators of the hypoxic transcriptional response. Although highly related, they can activate distinct target genes. In this study, the protein domain and molecular mechanism important for HIF target gene specificity are determined. We demonstrate that although HIF-2 is unable to activate multiple endogenous HIF-1–specific target genes (e.g., glycolytic enzymes), HIF-2 still binds to their promoters in vivo and activates reporter genes derived from such targets. In addition, comparative analysis of the N-terminal DNA binding and dimerization domains of HIF-1 and HIF-2 does not reveal any significant differences between the two proteins. Importantly, replacement of the N-terminal transactivation domain (N-TAD) (but not the DNA binding domain, dimerization domain, or C-terminal transactivation domain [C-TAD]) of HIF-2 with the analogous region of HIF-1 is sufficient to convert HIF-2 into a protein with HIF-1 functional specificity. Nevertheless, both the N-TAD and C-TAD are important for optimal HIF transcriptional activity. Additional experiments indicate that the ETS transcription factor ELK is required for HIF-2 to activate specific target genes such as Cited-2, EPO, and PAI-1. These results demonstrate that the HIF- TADs, particularly the N-TADs, confer HIF target gene specificity, by interacting with additional transcriptional cofactors.
The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).
Present address: Department of Craniofacial Biology, Mail Stop 8120, RC1 South, Room 11103, University of Colorado at Denver and Health Sciences Center, 12801 East 17th Avenue, P.O. Box 6511, Aurora, CO 80045.
Address correspondence to: M. Celeste Simon (celeste2{at}mail.med.upenn.edu).
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