HIF-1α induces cell cycle arrest by functionally counteracting Myc
HIF-1α induces cell cycle arrest by functionally counteracting Myc
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DOI：
10.1038/sj.emboj.7600196
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发表时间：
2004-05-05
期刊：
影响因子：
11.4
通讯作者：
Huang, LE
中科院分区：
文献类型：
--
作者：
Koshiji, M;Kageyama, Y;Huang, LE
缺氧诱导血管生成和糖酵解以促进细胞生长和存活，也导致生长停滞和凋亡。HIF-1 α是一种碱性螺旋-环-螺旋PAS转录因子，在低氧环境下通过上调多种基因表达而发挥氧稳态的主要调节作用。尽管遗传学研究表明缺氧诱导的生长停滞和p21（cip 1）激活需要HIF-1 α，p21（cip 1）是控制细胞周期检查点的关键细胞周期蛋白依赖性激酶抑制剂，但p21（cip 1）激活的潜在机制一直是难以捉摸的。在这里，我们证明了HIF-1 α，即使在缺氧信号的情况下，诱导细胞周期停滞的功能抵消Myc，从而解抑制p21（cip 1）。HIF-1 α拮抗作用是通过取代与p21（cip 1）启动子结合的Myc介导的。无论是HIF-1 α的转录活性，也不是它的DNA结合是必不可少的细胞周期阻滞，表明HIF-1 α的不同作用。与Myc的拮抗作用一致，HIF-1 α也下调Myc激活的基因，如hTERT和BRCA 1。因此，我们认为Myc是一个新的HIF-1 α通路的组成部分，该通路调节一组不同的Myc靶基因对缺氧的反应。
Hypoxia induces angiogenesis and glycolysis for cell growth and survival, and also leads to growth arrest and apoptosis. HIF-1alpha, a basic helix-loop-helix PAS transcription factor, acts as a master regulator of oxygen homeostasis by upregulating various genes under low oxygen tension. Although genetic studies have indicated the requirement of HIF-1alpha for hypoxia-induced growth arrest and activation of p21(cip1), a key cyclin-dependent kinase inhibitor controlling cell cycle checkpoint, the mechanism underlying p21(cip1) activation has been elusive. Here we demonstrate that HIF-1alpha, even in the absence of hypoxic signal, induces cell cycle arrest by functionally counteracting Myc, thereby derepressing p21(cip1). The HIF-1alpha antagonism is mediated by displacing Myc binding from p21(cip1) promoter. Neither HIF-1alpha transcriptional activity nor its DNA binding is essential for cell cycle arrest, indicating a divergent role for HIF-1alpha. In keeping with its antagonism of Myc, HIF-1alpha also downregulates Myc-activated genes such as hTERT and BRCA1. Hence, we propose that Myc is an integral part of a novel HIF-1alpha pathway, which regulates a distinct group of Myc target genes in response to hypoxia.