Deletion of the oxygen-dependent degradation domain results in impaired transcriptional activity of hypoxia-inducible factors.

Hypoxia-inducible factors (HIF1α/HIF2α) are key transcription factors that promote angiogenesis. The overexpression of degradation-resistant HIF mutants is considered a promising pro-angiogenic therapeutic tool. We compared the transcriptional activity of HIF1α/HIF2α mutants that obtained their resistance to oxygen-dependent degradation either by deletion of their entire oxygen-dependent degradation (ODD) domain or by replacement of prolyl residues that are crucial for oxygen-dependent degradation. Although all HIF mutants translocated into the nucleus, HIF1α and HIF2α mutants inclosing the point mutations were significantly more effective in trans-activating the target gene VEGF and in inducing tube formation of endothelial cells than mutants lacking the complete ODD domain.