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Blood, 1 April 2007, Vol. 109, No. 7, pp. 2693-2699. Prepublished online as a Blood First Edition Paper on November 16, 2006; DOI 10.1182/blood-2006-08-041830. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-08-041830v1 109/7/2693    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chen, J.-J. Search for Related Content PubMed PubMed Citation Articles by Chen, J.-J. Related Collections Red Cells Apoptosis Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  REVIEW ARTICLE Regulation of protein synthesis by the heme-regulated eIF2 kinase: relevance to anemias Jane-Jane Chen1 1 Harvard–Massachusetts Institute of Technology (MIT) Division of Health Sciences and Technology (HST), MIT, Cambridge, MA During erythroid differentiation and maturation, it is critical that the 3 components of hemoglobin, -globin, ß-globin, and heme, are made in proper stoichiometry to form stable hemoglobin. Heme-regulated translation mediated by the heme-regulated inhibitor kinase (HRI) provides one major mechanism that ensures balanced synthesis of globins and heme. HRI phosphorylates the -subunit of eukaryotic translational initiation factor 2 (eIF2) in heme deficiency, thereby inhibiting protein synthesis globally. In this manner, HRI serves as a feedback inhibitor of globin synthesis by sensing the intracellular concentration of heme through its heme-binding domains. HRI is essential not only for the translational regulation of globins, but also for the survival of erythroid precursors in iron deficiency. Recently, the protective function of HRI has also been demonstrated in murine models of erythropoietic protoporphyria and ß-thalassemia. In these 3 anemias, HRI is essential in determining red blood cell size, number, and hemoglobin content per cell. Translational regulation by HRI is critical to reduce excess synthesis of globin proteins or heme under nonoptimal disease states, and thus reduces the severity of these diseases. The protective role of HRI may be more common among red cell disorders. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Lynch, Y. Fukuda, P. Krishnamurthy, G. Du, and J. D. 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Ron Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2{alpha}) dephosphorylation in mammalian development PNAS, February 10, 2009; 106(6): 1832 - 1837. [Abstract] [Full Text] [PDF] J. Narasimhan, B. R. Joyce, A. Naguleswaran, A. T. Smith, M. R. Livingston, S. E. Dixon, I. Coppens, R. C. Wek, and W. J. Sullivan Jr. Translation Regulation by Eukaryotic Initiation Factor-2 Kinases in the Development of Latent Cysts in Toxoplasma gondii J. Biol. Chem., June 13, 2008; 283(24): 16591 - 16601. [Abstract] [Full Text] [PDF] L. B. Gardner Hypoxic Inhibition of Nonsense-Mediated RNA Decay Regulates Gene Expression and the Integrated Stress Response Mol. Cell. Biol., June 1, 2008; 28(11): 3729 - 3741. [Abstract] [Full Text] [PDF] S. Liu, R. N.V.S. Suragani, A. Han, W. Zhao, N. C. Andrews, and J.-J. Chen Deficiency of heme-regulated eIF2{alpha} kinase decreases hepcidin expression and splenic iron in HFE-/- mice Haematologica, May 1, 2008; 93(5): 753 - 756. [Abstract] [Full Text] [PDF] J. F. Raven, D. Baltzis, S. Wang, Z. Mounir, A. I. Papadakis, H. Q. Gao, and A. E. Koromilas PKR and PKR-like Endoplasmic Reticulum Kinase Induce the Proteasome-dependent Degradation of Cyclin D1 via a Mechanism Requiring Eukaryotic Initiation Factor 2{alpha} Phosphorylation J. Biol. Chem., February 8, 2008; 283(6): 3097 - 3108. [Abstract] [Full Text] [PDF] Q. Su, S. Wang, H. Q. Gao, S. Kazemi, H. P. Harding, D. Ron, and A. E. Koromilas Modulation of the Eukaryotic Initiation Factor 2 {alpha}-Subunit Kinase PERK by Tyrosine Phosphorylation J. Biol. Chem., January 4, 2008; 283(1): 469 - 475. [Abstract] [Full Text] [PDF]

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