| Regulation of hemoglobin synthesis and proliferation of differentiating erythroid cells by heme-regulated eIF-2alpha kinase. | |
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MedLine Citation:
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PMID: 11050009 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Protein synthesis in reticulocytes depends on the availability of heme. In heme deficiency, inhibition of protein synthesis correlates with the activation of heme-regulated eIF-2alpha kinase (HRI), which blocks the initiation of protein synthesis by phosphorylating eIF-2alpha. HRI is a hemoprotein with 2 distinct heme-binding domains. Heme negatively regulates HRI activity by binding directly to HRI. To further study the physiological function of HRI, the wild-type (Wt) HRI and dominant-negative inactive mutants of HRI were expressed by retrovirus-mediated transfer in both non-erythroid NIH 3T3 and mouse erythroleukemic (MEL) cells. Expression of Wt HRI in 3T3 cells resulted in the inhibition of protein synthesis, a loss of proliferation, and eventually cell death. Expression of the inactive HRI mutants had no apparent effect on the growth characteristics or morphology of NIH 3T3 cells. In contrast, expression of 3 dominant-negative inactive mutants of HRI in MEL cells resulted in increased hemoglobin production and increased proliferative capacity of these cells upon dimethyl-sulfoxide induction of erythroid differentiation. These results directly demonstrate the importance of HRI in the regulation of protein synthesis in immature erythroid cells and suggest a role of HRI in the regulation of the numbers of matured erythroid cells. |
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Authors:
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J S Crosby; P J Chefalo; I Yeh; S Ying; I M London; P Leboulch; J J Chen |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Blood Volume: 96 ISSN: 0006-4971 ISO Abbreviation: Blood Publication Date: 2000 Nov |
Date Detail:
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Created Date: 2000-12-11 Completed Date: 2000-12-11 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 3241-8 Citation Subset: AIM; IM |
Affiliation:
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Harvard-Massachusetts Institute of Technology, Division of Health Sciences and Technology, Cambridge MA, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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3T3 Cells Animals Cell Differentiation / drug effects Cell Division / drug effects Cell Line Dimethyl Sulfoxide / pharmacology Enzyme Activation Heme / physiology* Hemoglobins / biosynthesis* Homeostasis Leukemia, Erythroblastic, Acute Mice Recombinant Proteins / metabolism Transfection Tumor Cells, Cultured eIF-2 Kinase / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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DK16272/DK/NIDDK NIH HHS; HL55435/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Hemoglobins; 0/Recombinant Proteins; 14875-96-8/Heme; 67-68-5/Dimethyl Sulfoxide; EC 2.7.11.1/eIF-2 Kinase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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