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P024The role of ERK1/2 in cellular responses to ER stress Nicola Darling and Simon J Cook Babraham Institute, Cambridge, United Kingdom The unfolded protein response (UPR) pathway responds to endoplasmic reticulum (ER) stress stimuli that cause protein oxidation, misfolding or aggregation. Mild or short term ER stress activates the UPR through IRE1, PERK or ATF6 to promote cell survival and adaptation. Following chronic ER stress, cells activate JNK and also up-regulate the bZip transcription factor CHOP to promote apoptosis via the expression of pro-apoptotic proteins such as BIM and PUMA. The RAF-MEK-ERK1/2 signalling pathway has previously been shown to protect cells from BIM-dependent death by promoting the phosphorylation, poly-ubiquitylation and degradation of BIMEL. This raises several questions. Are ERK1/2 activated during ER stress? If so, does this serve a protective function? Do tumour cells with de-regulated ERK1/2 activation use this pathway to prevent death induced by ER stress? We find that ERK1/2 is activated in response to the ER stressor thapsigargin (Tg), an inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). ERK1/2 activation is rapid and transient, preceding expression of CHOP, PARP cleavage and cell death. Despite previous reports, Tg actually caused little increase in the overall abundance of BIMEL. However, the transient activation of ERK1/2 did lead to BIMEL phosphorylation, which should tend to promote its turnover and so prevent any net accumulation of BIMEL. Using conditional kinases, specific inhibitors and tumour cells with de-regulated ERK1/2 activity we are testing the hypothesis that ERK1/2 activation serves a protective role by preventing Tg-induced accumulation of BIMEL.