Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
PLoS Genet. 2011 Jan 27;7(1):e1001285. doi: 10.1371/journal.pgen.1001285.
Hypoxia Inducible Factor-1 (HIF-1) is essential for mammalian development and is the principal transcription factor activated by low oxygen tensions. HIF-α subunit quantities and their associated activity are regulated in a post-translational manner, through the concerted action of a class of enzymes called Prolyl Hydroxylases (PHDs) and Factor Inhibiting HIF (FIH) respectively. However, alternative modes of HIF-α regulation such as translation or transcription are under-investigated, and their importance has not been firmly established. Here, we demonstrate that NF-κB regulates the HIF pathway in a significant and evolutionary conserved manner. We demonstrate that NF-κB directly regulates HIF-1β mRNA and protein. In addition, we found that NF-κB-mediated changes in HIF-1β result in modulation of HIF-2α protein. HIF-1β overexpression can rescue HIF-2α protein levels following NF-κB depletion. Significantly, NF-κB regulates HIF-1β (tango) and HIF-α (sima) levels and activity (Hph/fatiga, ImpL3/ldha) in Drosophila, both in normoxia and hypoxia, indicating an evolutionary conserved mode of regulation. These results reveal a novel mechanism of HIF regulation, with impact in the development of novel therapeutic strategies for HIF-related pathologies including ageing, ischemia, and cancer.
缺氧诱导因子-1（HIF-1）对于哺乳动物的发育是必不可少的，它是由低氧张力激活的主要转录因子。HIF-α亚基的数量及其相关活性通过一类称为脯氨酰羟化酶（PHD）和因子抑制 HIF（FIH）的酶的协同作用，以翻译后方式进行调节。然而，HIF-α的其他调节方式，如翻译或转录，研究不足，其重要性尚未得到明确证实。在这里，我们证明 NF-κB 以一种重要且进化上保守的方式调节 HIF 途径。我们证明 NF-κB 直接调节 HIF-1β mRNA 和蛋白质。此外，我们发现 NF-κB 介导的 HIF-1β 变化导致 HIF-2α 蛋白的调制。HIF-1β 的过表达可以在 NF-κB 耗竭后挽救 HIF-2α 蛋白水平。重要的是，NF-κB 在常氧和低氧条件下调节果蝇中的 HIF-1β（探戈）和 HIF-α（西玛）水平和活性（Hph/fatiga，ImpL3/ldha），表明存在一种进化上保守的调节模式。这些结果揭示了 HIF 调节的一种新机制，对包括衰老、缺血和癌症在内的与 HIF 相关的病理的新型治疗策略的发展具有影响。
