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ER Stress Signaling Pathways in Cell Survival and Death

  • Proteins destined for the secretory pathway are processed in the endoplasmic reticulum (ER) where a delicate balance exists between protein folding and degradation of terminally misfolded proteins. Different physiological as well as pathological stress conditions however, can lead to an imbalance between the ER protein folding capacity and protein load, giving rise to an accumulation of misfolded proteins in the ER lumen, a condition dubbed as ‘ER stress’. In an attempt to meet the increased folding demand, cells utilize a conserved signaling pathway, the unfolded protein response (UPR), which is initially charged to re-establish ER homeostasis and support survival. If this mechanism fails, persistent ER stress will eventually cause this cytoprotective UPR to switch into a cell death pathway that can activate mitochondrial apoptosis. As such, the dual function of the UPR in controlling cell fate may play a part in disease development and response to stress signals in conflicting ways. The lethal arm of the UPR may contribute to pathologies that are linked to unscheduled cell death, like diabetes and certain neurodegenerative diseases such as Alzheimer's and Parkinson’s, or be utilized by certain anticancer drugs to kill cancer cells. On the other hand, activation of the pro-survival function of the UPR may assist processes like tumorigenesis and chemoresistance, by endowing cancer cells with an increased capability to adapt to their hostile environment and to cope with cellular damage. Therefore, a better understanding of the different signaling pathways that emanate from the stressed ER and how their integration modulates cell fate decisions represents a crucial requirement to develop new strategies aimed at targeting the UPR for therapeutic purposes.

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Document Type:Part of a Book
Author:Tom Verfaillie, Richard Jäger, Afshin Samali, Patrizia Agostinis
Parent Title (English):Agostinis, Samali (Eds.): Endoplasmic Reticulum Stress in Health and Disease
First Page:41
Last Page:73
Place of publication:Dordrecht
Date of first publication:2012/08/08
Tag:Adaptation; Bcl-2 proteins; Calcium signaling; ER-mitochondria crosstalk; IRE1; Mitochondria associated ER membranes; Oxidative stress; PERK; Protein homeostasis; apoptosis; cell death; endoplasmic reticulum stress; unfolded protein response
Departments, institutes and facilities:Institut für funktionale Gen-Analytik (IFGA)
Dewey Decimal Classification (DDC):6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Entry in this database:2018/07/14