Regulation of autophagy by ATF4 in response to severe hypoxia
Regulation of autophagy by ATF4 in response to severe hypoxia
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DOI：
10.1038/onc.2010.191
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发表时间：
2010-08-05
期刊：
影响因子：
8
通讯作者：
Harris, A. L.
中科院分区：
文献类型：
--
作者：
Rzymski, T.;Milani, M.;Harris, A. L.
激活转录因子4(ATF4)是一种在严重缺氧条件下诱导的转录因子，是参与未折叠蛋白反应(UPR)的PERK途径的组成部分，UPR是保护细胞免受内质网(ER)应激的负面后果的过程。在这项研究中，我们使用小干扰RNA(SiRNA)和微阵列分析首次对癌细胞中受ATF4调控的基因进行了全基因组分析，以响应严重和长期的低氧应激。我们发现ATF4在内质网应激和低氧诱导的自噬扩张中是必需的。MAP1LC3B(LC3B)是自噬体膜的关键成分，在本研究中，我们证明了ATF4通过直接与LC3B启动子中的环状AMP反应元件结合位点来促进自噬，从而导致LC3B上调。以前，我们已经证明Bortezomib诱导ATF4稳定，然后上调LC3B的表达，并在激活自噬中发挥关键作用，保护细胞免受Bortezomib诱导的细胞死亡。我们还发现，严重的低氧可以稳定ATF4。在这项研究中，我们证明了严重缺氧导致内质网应激，并通过LC3作为一种生存机制诱导ATF4依赖的自噬。综上所述，我们发现ATF4在内质网应激的自噬调节中起着关键作用，并在UPR和自噬机制之间提供了直接的机制联系。Oncogene(2010)29,4424-4435；doi：10.1038/onc.2010.191；2010年5月31日在线发布
Activating transcription factor 4 (ATF4) is a transcription factor induced under severe hypoxia and a component of the PERK pathway involved in the unfolded protein response (UPR), a process that protects cells from the negative consequences of endoplasmic reticulum (ER) stress. In this study, we have used small interfering RNA (siRNA) and microarray analysis to provide the first whole-genome analysis of genes regulated by ATF4 in cancer cells in response to severe and prolonged hypoxic stress. We show that ATF4 is required for ER stress and hypoxia-induced expansion of autophagy. MAP1LC3B (LC3B) is a key component of the autophagosomal membrane, and in this study we demonstrate that ATF4 facilitates autophagy through direct binding to a cyclic AMP response element binding site in the LC3B promoter, resulting in LC3B upregulation. Previously, we have shown that Bortezomib-induced ATF4 stabilization, which then upregulated LC3B expression and had a critical role in activating autophagy, protecting cells from Bortezomib-induced cell death. We also showed that severe hypoxia stabilizes ATF4. In this study, we demonstrate that severe hypoxia leads to ER stress and induces ATF4-dependent autophagy through LC3 as a survival mechanism. In summary, we show that ATF4 has a key role in the regulation of autophagy in response to ER stress and provide a direct mechanistic link between the UPR and the autophagic machinery. Oncogene (2010) 29, 4424-4435; doi: 10.1038/onc.2010.191; published online 31 May 2010