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PERK-dependent regulation of IAP translation during ER stress

Oncogene volume 28, pages 910–920 (2009)Cite this article

Abstract

Exposure of cells to endoplasmic reticulum (ER) stress leads to activation of phosphatidylinositol 3-kinase (PI3K)–Akt signaling pathway and transcriptional induction of the inhibitor of apoptosis family of proteins. One of the proximal effectors of the ER stress response, the PKR-like ER kinase (PERK), leads to cellular adaptation to stress by multiple mechanisms, including attenuation of protein synthesis and transcriptional induction of pro-survival genes. Although PERK activity leads to cellular adaptation to ER stress, we now demonstrate that PERK activity also inhibits the ER stress-induced apoptotic program through the induction of cellular inhibitor of apoptosis (cIAP1 and cIAP2) proteins. This induction of IAPs occurs through both transcriptional and translational responses that are PERK dependent. Reintroduction of cIAP1 or cIAP2 expression into PERK-/- murine embryonic fibroblasts during ER stress delays the early onset of ER stress-induced caspase activation and apoptosis observed in these cells. Furthermore, we demonstrate that the activation of the PI3K–Akt pathway by ER stress is dependent on PERK, suggesting additional ways in which PERK activity protects cells from ER stress-induced apoptosis.

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Acknowledgements

We thank M Romero for technical assistance and X Yang for providing IAP expression vectors. This study was supported by a grant from the National Institutes of Health F32CA1238252 (EBM); P01 CA104838, a Leukemia & Lymphoma Scholar award and the Abramson Family Cancer Research Institute (JAD).

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Authors and Affiliations

  1. Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA

    R B Hamanaka & E Bobrovnikova-Marjon

  2. The Leonard and Madlyn Abramson Family Cancer Research Institute and Cancer Center, University of Pennsylvania, Philadelphia, PA, USA

    R B Hamanaka, E Bobrovnikova-Marjon & J A Diehl

  3. Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA

    X Ji & S A Liebhaber

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  1. R B Hamanaka
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Correspondence to J A Diehl.

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Hamanaka, R., Bobrovnikova-Marjon, E., Ji, X. et al. PERK-dependent regulation of IAP translation during ER stress. Oncogene 28, 910–920 (2009). https://doi.org/10.1038/onc.2008.428

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