The N-terminal transactivation domain confers target gene specificity of hypoxia-inducible factors HIF-1alpha and HIF-2alpha.

Authors:
Dr. Cheng-Jun Hu, PhD
Dr. Cheng-Jun Hu, PhD
University of Colorado
Associate Professor
Pulmonary hypertension
Aurora, CO | United States
Aneesa Sataur
Aneesa Sataur
University of Pennsylvania School of Medicine
United States
Liyi Wang
Liyi Wang
University of Colorado Anschutz Medical Campus
Hongqing Chen
Hongqing Chen
Fuzhou University
China

Mol Biol Cell 2007 Nov 5;18(11):4528-42. Epub 2007 Sep 5.

Abramson Family Cancer Research Institute,University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

The basic helix-loop-helix-Per-ARNT-Sim-proteins hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha 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-2alpha is unable to activate multiple endogenous HIF-1alpha-specific target genes (e.g., glycolytic enzymes), HIF-2alpha 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-1alpha and HIF-2alpha 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-2alpha with the analogous region of HIF-1alpha is sufficient to convert HIF-2alpha into a protein with HIF-1alpha 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-2alpha to activate specific target genes such as Cited-2, EPO, and PAI-1. These results demonstrate that the HIF-alpha TADs, particularly the N-TADs, confer HIF target gene specificity, by interacting with additional transcriptional cofactors.

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http://dx.doi.org/10.1091/mbc.e06-05-0419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2043574PMC
November 2007
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