Hubbi Maimon E, Semenza Gregg L
a Vascular Program; Institute for Cell Engineering; Johns Hopkins University School of Medicine ; Baltimore , MD , USA.
Autophagy. 2015;11(5):850-1. doi: 10.1080/15548627.2015.1037063.
Hypoxia has long been known to serve as a stimulus for cell cycle arrest. Hypoxia-mediated cell cycle arrest is mediated through the actions of HIF1α (hypoxia inducible factor 1, α subunit [basic helix-loop-helix transcription factor]), which has a nontranscriptional role as an inhibitor of MCM (minichromosome maintenance complex component) helicase activity. We identified chaperone-mediated autophagy as a pathway for selective degradation of HIF1α through lysosomes prior to the onset of DNA replication. CDK2 (cyclin-dependent kinase 2) mediates degradation of HIF1α at the G1/S transition, whereas CDK1 (cyclin-dependent kinase 1) increases HIF1α levels and transcriptional activity prior to the onset of G1 phase. Lysosomal inhibitors induce cell cycle arrest, which is recovered by knockdown of HIF1α and EPAS1/HIF2α. These findings establish lysosomes as essential regulators of cell cycle progression through the degradation of HIF1α.
长期以来，人们一直认为缺氧是细胞周期停滞的一种刺激因素。缺氧介导的细胞周期停滞是通过缺氧诱导因子1α（HIF1α，即缺氧诱导因子1的α亚基[碱性螺旋-环-螺旋转录因子]）的作用介导的，HIF1α作为微小染色体维持复合物组分（MCM）解旋酶活性的抑制剂具有非转录作用。我们发现伴侣介导的自噬是在DNA复制开始之前通过溶酶体选择性降解HIF1α的一条途径。细胞周期蛋白依赖性激酶2（CDK2）在G1/S期转换时介导HIF1α的降解，而细胞周期蛋白依赖性激酶1（CDK1）在G1期开始之前增加HIF1α的水平和转录活性。溶酶体抑制剂诱导细胞周期停滞，通过敲低HIF1α和内皮 PAS 结构域蛋白1/缺氧诱导因子2α（EPAS1/HIF2α）可恢复细胞周期停滞。这些发现表明溶酶体通过降解HIF1α是细胞周期进程的重要调节因子。
