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

被引:558
作者
van Uden, Patrick [1 ]
Kenneth, Niall S. [1 ]
Rocha, Sonia [1 ]
机构
[1] Univ Dundee, Wellcome Trust Ctr Gene Regulat & Express, Dundee DD1 5EH, Scotland
基金
英国医学研究理事会; 英国惠康基金; 英国生物技术与生命科学研究理事会;
关键词
hypoxia; hypoxia-inducible factor 1 (HIF-1); nuclear factor kappa B (NF-kappa B); tumour necrosis factor (TNF);
D O I
10.1042/BJ20080476
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
HIF (hypoxia-inducible factor) is the main transcription factor activated by low oxygen tensions. HIF-1 alpha (and other a 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-1 alpha stabilization is also found in non-hypoxic conditions through an unknown mechanism. In the present study, we demonstrate that NF-kappa B (nuclear factor kappa B) is a direct modulator of HIF-1 alpha expression. The HIF-1 alpha promoter is responsive to selective NF-kappa B subunits. siRNA (small interfering RNA) studies for individual NF-kappa B members revealed differential effects on HIF-1 alpha mRNA levels, indicating that NF-kappa B can regulate basal HIF-1 alpha expression. Finally, when endogenous NF-kappa B is induced by TNF alpha (tumour necrosis factor alpha) treatment, HIF-1 alpha levels also change in an NF-kappa B-dependent manner. In conclusion, we find that NF-kappa B can regulate basal TNF alpha and, in certain circumstances, the hypoxia-induced HIF-1 alpha.
引用
收藏
页码:477 / 484
页数:8
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