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An initial phase of JNK activation inhibits cell death early in the endoplasmic reticulum stress response

Brown, M.; Strudwick, N.; Suwara, M.; Sutcliffe, L.K.; Mihai, A.D.; Ali, A.A.; Watson, J.N.; Schröder, M.

An initial phase of JNK activation inhibits cell death early in the endoplasmic reticulum stress response Thumbnail


Authors

M. Brown

N. Strudwick

M. Suwara

L.K. Sutcliffe

A.D. Mihai

A.A. Ali

J.N. Watson



Abstract

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR). In mammalian cells, UPR signals generated by several ER membrane resident proteins, including the bifunctional protein kinase endoribonuclease IRE1α, control cell survival and the decision to execute apoptosis. Processing of XBP1 mRNA by the RNase domain of IRE1α promotes survival of ER stress, while activation of the mitogen-activated protein kinase JNK by IRE1α late in the ER stress response promotes apoptosis. Here we show that activation of JNK in the ER stress response precedes activation of XBP1. This activation of JNK is dependent on IRE1α and TRAF2 and coincides with JNK-dependent induction of expression of several antiapoptotic genes, including cIAP1, cIAP2, XIAP, and BIRC6. ER-stressed jnk1−/− jnk2−/− mouse embryonic fibroblasts (MEFs) display more pronounced mitochondrial permeability transition and increased caspase 3/7 activity compared to wild type MEFs. Caspase 3/7 activity is also elevated in ER-stressed ciap1−/− ciap2−/−, and xiap−/− MEFs. These observations suggest that JNK-dependent transcriptional induction of several inhibitors of apoptosis contributes to inhibiting apoptosis early in the ER stress response.

Citation

Brown, M., Strudwick, N., Suwara, M., Sutcliffe, L., Mihai, A., Ali, A., …Schröder, M. (2016). An initial phase of JNK activation inhibits cell death early in the endoplasmic reticulum stress response. Journal of Cell Science, 129(12), 2317-2328. https://doi.org/10.1242/jcs.179127

Journal Article Type Article
Acceptance Date Apr 20, 2016
Online Publication Date Apr 27, 2016
Publication Date Apr 27, 2016
Deposit Date Apr 20, 2016
Publicly Available Date Apr 27, 2017
Journal Journal of Cell Science
Print ISSN 0021-9533
Electronic ISSN 1477-9137
Publisher The Company of Biologists
Peer Reviewed Peer Reviewed
Volume 129
Issue 12
Pages 2317-2328
DOI https://doi.org/10.1242/jcs.179127
Public URL https://durham-repository.worktribe.com/output/1406551

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