Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins

D Thomas Rutkowski; Stacey M Arnold; Corey N Miller; Jun Wu; Jack Li; Kathryn M Gunnison; Kazutoshi Mori; Amir A Sadighi Akha; David Raden; Randal J Kaufman

doi:10.1371/journal.pbio.0040374

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Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins

Journal article

Open access

Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins

D Thomas Rutkowski, Stacey M Arnold, Corey N Miller, Jun Wu, Jack Li, Kathryn M Gunnison, Kazutoshi Mori, Amir A Sadighi Akha, David Raden and Randal J Kaufman

PLoS biology, Vol.4(11), pp.e374-2041

11/2006

DOI: 10.1371/journal.pbio.0040374

PMCID: PMC1634883

PMID: 17090218

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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.

Signal Transduction

Protein Folding

Phenotype

Models, Theoretical

Cell Proliferation

Cells, Cultured

Endoplasmic Reticulum - physiology

Endoplasmic Reticulum - metabolism

Protein Denaturation - physiology

RNA, Messenger - metabolism

Adaptation, Biological - physiology

Apoptosis Regulatory Proteins - metabolism

Animals

Models, Biological

Stress, Physiological - metabolism

Mice

Apoptosis - physiology

Heat-Shock Proteins - physiology

Cell Survival - physiology

Details

Title: Subtitle: Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins
Creators: D Thomas Rutkowski - Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, Michigan, USA
Stacey M Arnold
Corey N Miller - University of Michigan
Jun Wu
Jack Li
Kathryn M Gunnison
Kazutoshi Mori
Amir A Sadighi Akha
David Raden
Randal J Kaufman
Resource Type: Journal article
Publication Details: PLoS biology, Vol.4(11), pp.e374-2041
DOI: 10.1371/journal.pbio.0040374
PMID: 17090218
PMCID: PMC1634883
NLM abbreviation: PLoS Biol
ISSN: 1544-9173
eISSN: 1545-7885
Grant note: R01 DK042394 / NIDDK NIH HHS\nR01 HL052173 / NHLBI NIH HHS\nR01 GM075297 / NIGMS NIH HHS\nR01 HL052173-06 / NHLBI NIH HHS
Language: English
Date published: 11/2006
Academic Unit: Anatomy and Cell Biology; Internal Medicine
Record Identifier: 9984094365102771

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