28 May 2008
hypoxia, hypoxia-inducible factor 1 (HIF-1), nuclear factor κB (NF-κB), tumour necrosis factor (TNF), ChIP, chromatin immunoprecipitation, EMSA, electrophoretic mobility-shift assay, GLUT, glucose transporter, HEK, human embryonic kidney, HIF, hypoxia-inducible factor, IκB, inhibitor of nuclear factor κB, IKK, IκB kinase, NF-κB, nuclear factor κB, PCNA, proliferating-cell nuclear antigen, PHD, prolyl hydroxylase, qRT-PCR, quantitative reverse transcriptase PCR, ROS, reactive oxygen species, RT, reverse transcriptase, siRNA, small interfering RNA, TNFα, tumour necrosis factor α, VEGF, vascular-endothelial growth factor
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.