Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2α) dephosphorylation in mammalian development
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Diverse cellular stress responses are linked to phosphorylation of serine 51 on the alpha subunit of translation initiation factor 2. The resultant attenuation of protein synthesis and activation of gene expression figure heavily in the adaptive response to stress, but dephosphorylation of eIF2(αP), which terminates signaling in this pathway, is less well understood. GADD34 and CReP, the products of the related mammalian genes Ppp1r15a and Ppp1r15b , can recruit phosphatase catalytic subunits of the PPP1 class to eIF2(αP), but the significance of their contribution to its dephosphorylation has not been explored systematically. Here we report that unlike Ppp1r15a mutant mice, which are superficially indistinguishable from wild type, Ppp1r15b −/− mouse embryos survive gestation but exhibit severe growth retardation and impaired erythropoiesis, and loss of both Ppp1r15 genes leads to early embryonic lethality. These loss-of-function phenotypes are rescued by a mutation, Eif2a S51A , that prevents regulated phosphorylation of eIF2α. These findings reveal that the essential process of eIF2(αP) dephosphorylation is the predominant role of PPP1R15 proteins in mammalian development.
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Protein synthesis is essential for normal development, and blocking dephosphorylation of eIF2α in mice results in severe growth restriction and early embryonic lethality.
“Protein synthesis is essential for normal development, and blocking dephosphorylation of eIF2α in mice results in severe growth restriction and early embryonic lethality (241).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [241]
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- Authors
- Harding, H. P., Zhang, Y., Scheuner, D., Chen, J.-J., Kaufman, R. J., & Ron, D.
- Affiliations
- New York University (US)
- Departments of Biological Chemistry and
- Harvard University (US)
- Howard Hughes Medical Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-02-10
- Volume
- 106
- Issue
- 6
- Pages
- 1832-1837
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2644123
- OpenAlex
- W2080666240
- Cited by
- 267
- References
- 44
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 18 · 2023: 20 · 2022: 18 · 2021: 21 · 2020: 20 · 2019: 12 · 2018: 24 · 2017: 19 · 2016: 14 · 2015: 25 · 2014: 10 · 2013: 8 · 2012: 18
- FWCI
- 5.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- York University
- National Institutes of Health (DK47119)
- National Heart, Lung, and Blood Institute (HL 52173, R01HL052173, P01HL057346)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK042394, DK42394, DK-47119, R37DK047119, R01DK047119, R37DK042394)
- National Institute of Environmental Health Sciences (ES 08681, R01ES008681)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- eIF2α dephosphorylation, PPP1R15A, GADD34, CReP, protein phosphatase 2A, embryonic lethality, growth retardation, erythropoiesis, stress response, mouse knockout
- MeSH terms
- Animals, Antigens, Differentiation, Embryo, Mammalian, Erythropoiesis, Female, Fetal Death, Growth Disorders, Eukaryotic Initiation Factor-2, Cell Cycle Proteins, Growth and Development, Mice, Protein Phosphatase 1, Gene Knockout Techniques
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