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Cited by 267Endoplasmic Reticulum Stress and DiseaseRNA and protein synthesis mechanismsPI3K/AKT/mTOR signaling in cancer

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Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2α) dephosphorylation in mammalian development

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Harding, Heather P., Zhang, Yuhong, Scheuner, Donalyn, Chen, Jane-Jane, Kaufman, Randal J., Ron, David·2009·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0809632106PMC PMC2644123
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Abstract

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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Metadata

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)
ORCID
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
DOI
10.1073/pnas.0809632106
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
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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