Regulation of hypoxia-inducible factor-1alpha by NF-kappaB.
HIF (hypoxia-inducible factor) is the main transcription factor activated by low oxygen tensions. HIF-1alpha (and other alpha 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-1alpha stabilization is also found in non-hypoxic conditions through an unknown mechanism. In the present study, we demonstrate that NF-kappaB (nuclear factor kappaB) is a direct modulator of HIF-1alpha expression. The HIF-1alpha promoter is responsive to selective NF-kappaB subunits. siRNA (small interfering RNA) studies for individual NF-kappaB members revealed differential effects on HIF-1alpha mRNA levels, indicating that NF-kappaB can regulate basal HIF-1alpha expression. Finally, when endogenous NF-kappaB is induced by TNFalpha (tumour necrosis factor alpha) treatment, HIF-1alpha levels also change in an NF-kappaB-dependent manner. In conclusion, we find that NF-kappaB can regulate basal TNFalpha and, in certain circumstances, the hypoxia-induced HIF-1alpha.
van Uden
Patrick
P
College of Life Sciences, Wellcome Trust Centre for Gene Regulation and Expression, MSI/WTB/JBC Complex, Dow Street, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Kenneth
Niall S
NS
Rocha
Sonia
S
D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering