ER stress and distinct outputs of the IRE1 alpha RNase control proliferation and senescence in response to oncogenic Ras

作者：Blazanin Nicholas; Son Jeongin; Craig Lucas Alayna B; John Christian L; Breech Kyle J; Podolsky Michael A; Glick Adam B^*

来源：Proceedings of the National Academy of Sciences, 2017, 114(37): 9900-9905.

DOI：10.1073/pnas.1701757114

• oncogene-induced senescence
• ER stress
• IRE1 alpha
• Ras
• ID1

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.

• 出版日期2017-9-12