ArticleBlood2012
Heme-regulated eIF2α kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis.
Article in Blood, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 100 papers.
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Who cites it
100 citing papers in PubMed, 161 citations in OpenAlex.
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- HRI protein kinase in cytoplasmic heme sensing and mitochondrial stress response: Relevance to hematological and mitochondrial diseases.The Journal of biological chemistry · 2025Review
- Ribosomal protein deficiencies linked to Diamond-Blackfan anemia induce distinctive alterations of ATF4 expression.iScience · 2025Article
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- An unexpected role for the ketogenic diet in triggering tumor metastasis by modulating BACH1-mediated transcription.Science advances · 2024Article
- ATF4 in cellular stress, ferroptosis, and cancer.Archives of toxicology · 2024Review
- Gene Expression Profiling Reveals Fundamental Sex-Specific Differences in SIRT3-Mediated Redox and Metabolic Signaling in Mouse Embryonic Fibroblasts.International journal of molecular sciences · 2024Article
- ATF4 Signaling in HIV-1 Infection: Viral Subversion of a Stress Response Transcription Factor.Biology · 2024Review
40 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Heme-regulated eIF2α kinase (Hri) is necessary for balanced synthesis of heme and globin. In addition, Hri deficiency exacerbates the phenotypic severity of β-thalassemia intermedia in mice. Activation of Hri during heme deficiency and in β-thalassemia increases eIF2α phosphorylation and inhibits globin translation. Under endoplasmic reticulum stress and nutrient starvation, eIF2α phosphorylation also induces the Atf4 signaling pathway to mitigate stress. Although the function of Hri in regulating globin translation is well established, its role in Atf4 signaling in erythroid precursors is not known. Here, we report the role of the Hri-activated Atf4 signaling pathway in reducing oxidative stress and in promoting erythroid differentiation during erythropoiesis. On acute oxidative stress, Hri(-/-) erythroblasts suffered from increased levels of reactive oxygen species (ROS) and apoptosis. During chronic iron deficiency in vivo, Hri is necessary both to reduce oxidative stress and to promote erythroid differentiation. Hri(-/-) mice developed ineffective erythropoiesis during iron deficiency with inhibition of differentiation at the basophilic erythroblast stage. This inhibition is recapitulated during ex vivo differentiation of Hri(-/-) fetal liver erythroid progenitors. Importantly, the Hri-eIF2αP-Atf4 pathway was activated and required for erythroid differentiation. We further demonstrate the potential of modulating Hri-eIF2αP-Atf4 signaling with chemical compounds as pharmaceutical therapies for β-thalassemia.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.