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Publication : Heme-regulated eIF2α kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis.

First Author  Suragani RN Year  2012
Journal  Blood Volume  119
Issue  22 Pages  5276-84
PubMed ID  22498744 Mgi Jnum  J:185147
Mgi Id  MGI:5427532 Doi  10.1182/blood-2011-10-388132
Citation  Suragani RN, et al. (2012) Heme-regulated eIF2alpha kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis. Blood 119(22):5276-84
abstractText  Heme-regulated eIF2alpha kinase (Hri) is necessary for balanced synthesis of heme and globin. In addition, Hri deficiency exacerbates the phenotypic severity of beta-thalassemia intermedia in mice. Activation of Hri during heme deficiency and in beta-thalassemia increases eIF2alpha phosphorylation and inhibits globin translation. Under endoplasmic reticulum stress and nutrient starvation, eIF2alpha 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-eIF2alphaP-Atf4 pathway was activated and required for erythroid differentiation. We further demonstrate the potential of modulating Hri-eIF2alphaP-Atf4 signaling with chemical compounds as pharmaceutical therapies for beta-thalassemia.
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