Hypoxia-inducible factor-1α (HIF-1α) escapes O 2 -driven proteasomal degradation irrespective of its subcellular localization: nucleus or cytoplasm

Eukaryotic cells sense oxygen and adapt to hypoxia by regulating a number of genes. Hypoxia‐inducible factor 1 (HIF‐1) is the ‘master’ in this pleiotypic response. HIF‐1 comprises two members of the basic helix–loop–helix transcription factor family, HIF‐1α and HIF‐1β. The HIF‐1α protein is subject to drastic O 2 ‐dependent proteasomal control. However, the signalling components regulating the ‘switch’ for ‘escaping’ proteasomal degradation under hypoxia are still largely unknown. The rapid nuclear translocation of HIF‐1α could represent an efficient way to escape from this degradation. We therefore asked, where in the cell is HIF‐1α degraded? To address this question, we trapped HIF‐1α either in the cytoplasm, by fusing HIF‐1α to the cytoplasmic domain of the Na + ‐H + exchanger (NHE‐1), or in the nucleus, by treatment with leptomycin B. Surprisingly, we found that HIF‐1α is stabilized by hypoxia and undergoes O 2 ‐dependent proteasomal degradation with an identical half‐life (5–8 min) in both cellular compartments. Therefore, HIF‐1α entry into the nucleus is not, as proposed, a key event that controls its stability. This result markedly contrasts with the mechanism that controls p53 degradation via MDM2.