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

ABSTRACT: 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? (IRE1?) endoribonuclease (RNase), a key mediator of the UPR, cleaves Xbp1 mRNA to generate a potent transcription factor adaptive toward ER stress. However, IRE1? 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?. 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? RNase. Microarray analysis of IRE1?- 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? RNase target. Further, we demonstrate that Id1 degradation by IRE1? is essential for HRas-induced premature senescence. Together, our studies point to IRE1? 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.

SUBMITTER: Blazanin N 

PROVIDER: S-EPMC5603998 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature