Adaptation to ER Stress Is Mediated by Differential Stabilities of Pro-Survival and Pro-Apoptotic mRNAs and Proteins

Abstract

The accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates a signaling cascade known as the unfolded protein response (UPR). Although activation of the UPR is well described, there is little sense of how the response, which initiates both apoptotic and adaptive pathways, can selectively allow for adaptation. Here we describe the reconstitution of an adaptive ER stress response in a cell culture system. Monitoring the activation and maintenance of representative UPR gene expression pathways that facilitate either adaptation or apoptosis, we demonstrate that mild ER stress activates all UPR sensors. However, survival is favored during mild stress as a consequence of the intrinsic instabilities of mRNAs and proteins that promote apoptosis compared to those that facilitate protein folding and adaptation. As a consequence, the expression of apoptotic proteins is short-lived as cells adapt to stress. We provide evidence that the selective persistence of ER chaperone expression is also applicable to at least one instance of genetic ER stress. This work provides new insight into how a stress response pathway can be structured to allow cells to avert death as they adapt. It underscores the contribution of posttranscriptional and posttranslational mechanisms in influencing this outcome.

Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma

“…We therefore hypothesised that the reduced ER stress response observed in BRAF mutant melanoma cells results from chronic ER stress that desensitizes them to further stress stimuli. 28 To test this hypothesis, we analysed the expression levels of ER stress markers in our extended panel of BRAF V600E melanoma cells compared with BRAF WT cells. As shown in Figure 2a, BRAF V600E melanoma cell lines displayed approximately twofold greater expression of mRNA coding for ERdj5, ERp57, ATF4 and Xbp-I 33 compared with BRAF wt cells, indicating that a mild but consistent induction of ER stress is conferred by an activating mutation in the BRAF protein kinase.…”

“…27 The accepted hypothesis is thus that activation of the UPR in cancer cells enables their adaption to such ER stress resulting in the resistance to apoptosis through the persistent expression of pro-survival instead of pro-apoptotic proteins. 28 Although under stress conditions, autophagy and ER stress seem to act in parallel, indeed they are closely related, because one can regulate the other and vice versa. In fact, ER stress is able to promptly stimulate autophagy, 26 whereas autophagy selectively removes the membranes of the endoplasmic reticulum at the end of the UPR, although the molecular mechanisms are still largely unclear.…”

Dickkopf-1 activates cell death in MDA-MB435 melanoma cells

“…These observations are consistent with results published by others. However, UPR induces adaptive response which would favor cell survival due to inhibition of apoptosis [21]. We cultured cells for 2.5-3 months before injection into animals which would provide sufficient time for adaptation and inhibition of apoptosis.…”

Approaches to imaging unfolded secretory protein stress in living cells

“…For example, the protein CHOP is upregulated during ER stress [26]. CHOP is a transcription factor that activates expression of genes involved in protection of cells from stress [67] and induction of apoptosis [5]. CHOP expression is regulated by the UPR via increased translation of ATF4 [26].…”