Research Papers:

The eIF2α serine 51 phosphorylation-ATF4 arm promotes HIPPO signaling and cell death under oxidative stress

Kamindla Rajesh, Jothilatha Krishnamoorthy, Jyotsana Gupta, Urszula Kazimierczak, Andreas I. Papadakis, Zhilin Deng, Shuo Wang, Shinji Kuninaka and Antonis E. Koromilas _

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Oncotarget. 2016; 7:51044-51058. https://doi.org/10.18632/oncotarget.10480

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Kamindla Rajesh1, Jothilatha Krishnamoorthy1,*, Jyotsana Gupta1,*, Urszula Kazimierczak1,2, Andreas I. Papadakis1, Zhilin Deng1, Shuo Wang1, Shinji Kuninaka3 and Antonis E. Koromilas1,4

1 Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada

2 Department of Cancer Immunology, Poznan University of Medical Sciences, Poznan, Poland

3 Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan

4 Department of Oncology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada

* These authors have contributed equally to this study

Correspondence to:

Antonis E. Koromilas, email:

Keywords: translation initiation factor eIF2, protein phosphorylation, activating transcription factor 4, mRNA translation, large tumor suppressor 1

Received: June 16, 2016 Accepted: June 23, 2016 Published: July 07, 2016


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.

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