The DOI matches its Crossref record; 66 of the 66 references it cites were found in a registry or an index.
ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death
Open accessAbstract
Protein misfolding in the endoplasmic reticulum (ER) leads to cell death through PERK-mediated phosphorylation of eIF2α, although the mechanism is not understood. ChIP-seq and mRNA-seq of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), key transcription factors downstream of p-eIF2α, demonstrated that they interact to directly induce genes encoding protein synthesis and the unfolded protein response, but not apoptosis. Forced expression of ATF4 and CHOP increased protein synthesis and caused ATP depletion, oxidative stress and cell death. The increased protein synthesis and oxidative stress were necessary signals for cell death. We show that eIF2α-phosphorylation-attenuated protein synthesis, and not Atf4 mRNA translation, promotes cell survival. These results show that transcriptional induction through ATF4 and CHOP increases protein synthesis leading to oxidative stress and cell death. The findings suggest that limiting protein synthesis will be therapeutic for diseases caused by protein misfolding in the ER.
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“Prolonged or extreme ER stress, leading to an overload of the repair and degradation machineries, triggers cellular apoptosis (Han et al, 2013; Sano & Reed, 2013).”
From Differential dynamics of the mammalian mRNA and protein expression response to misfolding stress (2016) · cites this paper as Han et al, 2013
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Cites
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Self-citationProtein misfolding in the endoplasmic reticulum as a conduit to human disease
Wang, M., & Kaufman, R. J. (2016) · Nature · doi:10.1038/nature17041 · Cited by 1,630
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Self-citationCellular Adaptation to Hypoxia through Hypoxia Inducible Factors and beyond
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Metadata
- Authors
- Han, J., Back, S. H., Hur, J., Lin, Y.-H., Gildersleeve, R., Shan, J., Yuan, C. L., Krokowski, D., Wang, S., Hatzoglou, M., Kilberg, M. S., Sartor, M. A., & Kaufman, R. J.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- University of Michigan (US)
- University of Florida (US)
- Case Western Reserve University (US)
- Corresponding author
- Kaufman, Randal J.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2013-04-28
- Volume
- 15
- Issue
- 5
- Pages
- 481-490
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC3692270
- OpenAlex
- W2074471441
- Cited by
- 1,691
- References
- 66
- Citations by year
- 2026: 102 · 2025: 136 · 2024: 140 · 2023: 136 · 2022: 153 · 2021: 136 · 2020: 153 · 2019: 123 · 2018: 127 · 2017: 118 · 2016: 117 · 2015: 112 · 2014: 102 · 2013: 30
- FWCI
- 70.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Michigan
- National Heart, Lung, and Blood Institute (R01HL052173, HL 057346, P01HL057346, HL052173)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK088227, R01DK042394, R24DK093074, DK-042394, R01DK094729, DK092062, DK53307, DK088227, DK-094729, R01DK053307, DK60596, DK093074, R37DK060596, R01DK092062, R37DK042394, R01DK060596)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- endoplasmic reticulum stress, unfolded protein response, ATF4, CHOP, eIF2α phosphorylation, protein synthesis, oxidative stress, ATP depletion, cell death, transcriptional regulation, protein misfolding, apoptosis
- MeSH terms
- Adenosine Triphosphate, Animals, Binding Sites, Cell Survival, Gene Expression Regulation, Phosphorylation, Promoter Regions, Genetic, Protein Binding, RNA, Messenger, Transcription, Genetic, Protein Biosynthesis, Eukaryotic Initiation Factor-2, Cell Death, Reactive Oxygen Species, Protein Folding, Protein Interaction Mapping, Chromatin Immunoprecipitation, Mice, Activating Transcription Factor 4, Transcription Factor CHOP, Unfolded Protein Response, Endoplasmic Reticulum Stress
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