The dietary flavonoid quercetin modulates HIF-1α activity in endothelial cells

被引:53
作者
Wilson, WJ [1 ]
Poellinger, L [1 ]
机构
[1] Karolinska Inst, Med Nobel Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden
关键词
HIF-1; alpha; bHLH-PAS; hypoxia; quercetin; flavonoid; kinase inhibitor; enclothelial cells; protein regulation; green fluorescent protein; signal transduction;
D O I
10.1016/S0006-291X(02)00244-9
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
The mechanism of activation of the transcription factor hypoxia-inducible factor-1 (HIF-1) has been studied extensively. Under normal cellular oxygen conditions protein levels of the alpha subunit (HIF-1alpha) are kept low due to massive ubiquitination and subsequent proteosomal degradation. However, during hypoxia ubiquitination is inhibited, causing stabilisation of the HIF-1alpha protein. HIF-1alpha can then translocate to the nucleus and facilitate transcription of numerous target genes, the majority of which are involved in glycolysis and angiogenesis via heterodimerisation with the beta subunit (HIF-1beta/ARNT). Until now hypoxia has been the only naturally occurring signal shown to activate this transcription factor. We report here that the dietary flavonoid quercetin ;lso activates HIF-1alpha in all steps of its activation pathway, in a manner similar to hypoxia. We found that quercetin, an inhibitor of Ser/Thr kinases, stabilises HIF-1alpha and causes nuclear localisation of the protein in a transcriptionally active state. Taken together these results strongly indicate that the dietary flavonoid quercetin regulates HIF-1 function at normal oxygen concentrations. (C) 2002 Elsevier Science (USA). All rights reserved.
引用
收藏
页码:446 / 450
页数:5
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