ER stress and distinct outputs of the IRE1α RNase control proliferation and senescence in response to oncogenic Ras
ER stress and distinct outputs of the IRE1α RNase control proliferation and senescence in response to oncogenic Ras
复制标题
DOI：
10.1073/pnas.1701757114
复制
发表时间：
2017-09-12
影响因子：
11.1
通讯作者：
Glick, Adam B.
中科院分区：
文献类型：
--
作者：
Blazanin, Nicholas;Son, Jeongin;Glick, Adam B.
致癌 Ras 会导致原代细胞增殖，然后过早衰老，这是肿瘤发展的最初障碍。内质网（ER）应激和未折叠蛋白反应（UPR）在调节这两种细胞结果中的作用尚不清楚。在内质网应激期间，肌醇需要酶 1 α (IRE1 α) 核糖核酸内切酶 (RNase)（UPR 的关键介质），裂解 Xbp1 mRNA，产生适应内质网应激的有效转录因子。然而，IRE1 α 也会促进细胞死亡所必需的内质网定位 mRNA 的裂解和降解。在这里，我们发现致癌 HRas 会诱导 ER 应激和 IRE1 α 的激活。使用药理学、遗传学和 RNAi 方法减少 ER 应激或 Xbp1 剪接表明，这种适应性反应对于 HRas 诱导的增殖至关重要。矛盾的是，减少 ER 应激或 Xbp1 剪接会通过 IRE1 α RNase 的过度激活促进生长停滞和过早衰老。对 IRE1 α 和 XBP1 耗尽的细胞进行微阵列分析，使用 RNA 裂解测定进行验证，以及 5' RACE 鉴定出原癌碱性螺旋-环-螺旋转录因子 ID1 作为 IRE1 α RNase 靶标。此外，我们证明 Id1 被 IRE1 α 降解对于 HRas 诱导的过早衰老至关重要。总之，我们的研究表明 IRE1 α 是早期 Ras 表型转录后调控的重要节点，依赖于致癌信号以及肿瘤微环境传递的应激信号，并且可能是驱动逃避 Ras 诱导衰老的重要机制。
Oncogenic Ras causes proliferation followed by premature senescence in primary cells, an initial barrier to tumor development. The role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in regulating these two cellular outcomes is poorly understood. During ER stress, the inositol requiring enzyme 1 alpha (IRE1 alpha) endoribonuclease (RNase), a key mediator of the UPR, cleaves Xbp1 mRNA to generate a potent transcription factor adaptive toward ER stress. However, IRE1 alpha also promotes cleavage and degradation of ER-localized mRNAs essential for cell death. Here, we show that oncogenic HRas induces ER stress and activation of IRE1 alpha. Reduction of ER stress or Xbp1 splicing using pharmacological, genetic, and RNAi approaches demonstrates that this adaptive response is critical for HRas-induced proliferation. Paradoxically, reduced ER stress or Xbp1 splicing promotes growth arrest and premature senescence through hyperactivation of the IRE1 alpha RNase. Microarray analysis of IRE1 alpha- and XBP1-depleted cells, validation using RNA cleavage assays, and 5' RACE identified the prooncogenic basic helix-loop-helix transcription factor ID1 as an IRE1 alpha RNase target. Further, we demonstrate that Id1 degradation by IRE1 alpha is essential for HRas-induced premature senescence. Together, our studies point to IRE1 alpha as an important node for posttranscriptional regulation of the early Ras phenotype that is dependent on both oncogenic signaling as well as stress signals imparted by the tumor microenvironment and could be an important mechanism driving escape from Ras-induced senescence.