Brown, M. and Strudwick, N. and Suwara, M. and Sutcliffe, L. K. and Mihai, A. D. and Ali, A. A. and Watson, J. N. and 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). pp. 2317-2328.
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.
|Full text:||(AM) Accepted Manuscript|
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|Publisher Web site:||http://dx.doi.org/10.1242/jcs.179127|
|Date accepted:||20 April 2016|
|Date deposited:||21 April 2016|
|Date of first online publication:||27 April 2016|
|Date first made open access:||27 April 2017|
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