Kenneth Niall S, Mudie Sharon, van Uden Patrick, Rocha Sonia
College of Life Sciences, Wellcome Trust Centre for Gene Regulation and Expression, MSI/WTB/JBC Complex, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom.
J Biol Chem. 2009 Feb 13;284(7):4123-31. doi: 10.1074/jbc.M808491200. Epub 2008 Dec 19.
Hypoxia induces a variety of cellular responses such as cell cycle arrest, apoptosis, and autophagy. Most of these responses are mediated by the hypoxia-inducible factor-1alpha. To induce target genes, hypoxia-inducible factor-1alpha requires a chromatin environment conducive to allow binding to specific sequences. Here, we have studied the role of the chromatin-remodeling complex SWI/SNF in the cellular response to hypoxia. We find that SWI/SNF is required for several of the cellular responses induced by hypoxia. Surprisingly, hypoxia-inducible factor-1alpha is a direct target of the SWI/SNF chromatin-remodeling complex. SWI/SNF components are found associated with the hypoxia-inducible factor-1alpha promoter and modulation of SWI/SNF levels results in pronounced changes in hypoxia-inducible factor-1alpha expression and its ability to transactivate target genes. Furthermore, impairment of SWI/SNF function renders cells resistant to hypoxia-induced cell cycle arrest. These results reveal a previously uncharacterized dependence of hypoxia signaling on the SWI/SNF complex and demonstrate a new level of control over the hypoxia-inducible factor-1alpha system.
缺氧会引发多种细胞反应，如细胞周期停滞、凋亡和自噬。这些反应大多由缺氧诱导因子-1α介导。为了诱导靶基因，缺氧诱导因子-1α需要一个有利于其与特定序列结合的染色质环境。在此，我们研究了染色质重塑复合体SWI/SNF在细胞对缺氧反应中的作用。我们发现SWI/SNF是缺氧诱导的几种细胞反应所必需的。令人惊讶的是，缺氧诱导因子-1α是SWI/SNF染色质重塑复合体的直接靶点。发现SWI/SNF组分与缺氧诱导因子-1α启动子相关联，并且SWI/SNF水平的调节会导致缺氧诱导因子-1α表达及其激活靶基因能力的显著变化。此外，SWI/SNF功能的损害使细胞对缺氧诱导的细胞周期停滞产生抗性。这些结果揭示了缺氧信号传导以前未被表征的对SWI/SNF复合体的依赖性，并证明了对缺氧诱导因子-1α系统的新的控制水平。
