Download P024 The role of ERK1/2 in cellular responses to ER stress Nicola

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.