Regulation of hypoxia-inducible factor-1α by NF-κB

TLDR

HIF is the main transcription factor activated by low oxygen, with HIF‑1α tightly regulated at the protein level by prolyl hydroxylases, and while most knowledge comes from hypoxic stress, HIF‑1α stabilization also occurs in non‑hypoxic conditions via an unknown mechanism. In the present study, we demonstrate that NF‑κB (nuclear factor κB) is a direct modulator of HIF‑1α expression. The study shows that NF‑κB directly modulates HIF‑1α expression, with its promoter responsive to specific NF‑κB subunits, siRNA knockdown of individual members altering HIF‑1α mRNA levels, and TNFα‑induced NF‑κB activity changing HIF‑1α levels in an NF‑κB‑dependent manner, indicating regulation of basal and hypoxia‑induced HIF‑1α.

Abstract

HIF (hypoxia-inducible factor) is the main transcription factor activated by low oxygen tensions. HIF-1α (and other α subunits) is tightly controlled mostly at the protein level, through the concerted action of a class of enzymes called PHDs (prolyl hydroxylases) 1, 2 and 3. Most of the knowledge of HIF derives from studies following hypoxic stress; however, HIF-1α stabilization is also found in non-hypoxic conditions through an unknown mechanism. In the present study, we demonstrate that NF-κB (nuclear factor κB) is a direct modulator of HIF-1α expression. The HIF-1α promoter is responsive to selective NF-κB subunits. siRNA (small interfering RNA) studies for individual NF-κB members revealed differential effects on HIF-1α mRNA levels, indicating that NF-κB can regulate basal HIF-1α expression. Finally, when endogenous NF-κB is induced by TNFα (tumour necrosis factor α) treatment, HIF-1α levels also change in an NF-κB-dependent manner. In conclusion, we find that NF-κB can regulate basal TNFα and, in certain circumstances, the hypoxia-induced HIF-1α.