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The basic helix-loop-helix-Per-ARNT-Sim–proteins hypoxia-inducible factor (HIF)-1α and HIF-2α 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-2α is unable to activate multiple endogenous HIF-1α–specific target genes (e.g., glycolytic enzymes), HIF-2α 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-1α and HIF-2α 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 …