1. The eIF2α serine 51 phosphorylation-ATF4 arm promotes HIPPO signaling and cell death under oxidative stress
- Author
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Jyotsana Gupta, Shinji Kuninaka, Jothilatha Krishnamoorthy, Zhilin Deng, Antonis E. Koromilas, Kamindla Rajesh, Shuo Wang, Andreas I. Papadakis, and Urszula Kazimierczak
- Subjects
0301 basic medicine ,Programmed cell death ,mRNA translation ,Eukaryotic Initiation Factor-2 ,translation initiation factor eIF2 ,Protein Serine-Threonine Kinases ,Biology ,medicine.disease_cause ,Mice ,03 medical and health sciences ,large tumor suppressor 1 ,Cell Line, Tumor ,Serine ,medicine ,Animals ,Humans ,Hippo Signaling Pathway ,Protein phosphorylation ,Phosphorylation ,Mice, Knockout ,Genetics ,eIF2 ,Hippo signaling pathway ,Cell Death ,Cell growth ,Activating Transcription Factor 4 ,protein phosphorylation ,Cell biology ,Oxidative Stress ,030104 developmental biology ,Gene Expression Regulation ,Oncology ,Hippo signaling ,Oxidative stress ,Signal Transduction ,Research Paper - Abstract
The HIPPO pathway is an evolutionary conserved regulator of organ size that controls both cell proliferation and death. This pathway has an important role in mediating cell death in response to oxidative stress through the inactivation of Yes-associated protein (YAP) and inhibition of anti-oxidant gene expression. Cells exposed to oxidative stress induce the phosphorylation of the alpha (α) subunit of the translation initiation factor eIF2 at serine 51 (eIF2αP), a modification that leads to the general inhibition of mRNA translation initiation. Under these conditions, increased eIF2αP facilitates the mRNA translation of activating transcription factor 4 (ATF4), which mediates either cell survival and adaptation or cell death under conditions of severe stress. Herein, we demonstrate a functional connection between the HIPPO and eIF2αP-ATF4 pathways under oxidative stress. We demonstrate that ATF4 promotes the stabilization of the large tumor suppressor 1 (LATS1), which inactivates YAP by phosphorylation. ATF4 inhibits the expression of NEDD4.2 and WWP1 mRNAs under pro-oxidant conditions, which encode ubiquitin ligases mediating the proteasomal degradation of LATS1. Increased LATS1 stability is required for the induction of cell death under oxidative stress. Our data reveal a previously unidentified ATF4-dependent pathway in the induction of cell death under oxidative stress via the activation of LATS1 and HIPPO pathway.
- Published
- 2016