Document Detail

Regulation of hemoglobin synthesis and proliferation of differentiating erythroid cells by heme-regulated eIF-2alpha kinase.
MedLine Citation:
PMID:  11050009     Owner:  NLM     Status:  MEDLINE    
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.
J S Crosby; P J Chefalo; I Yeh; S Ying; I M London; P Leboulch; J J Chen
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Blood     Volume:  96     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  2000 Nov 
Date Detail:
Created Date:  2000-12-11     Completed Date:  2000-12-11     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  3241-8     Citation Subset:  AIM; IM    
Harvard-Massachusetts Institute of Technology, Division of Health Sciences and Technology, Cambridge MA, USA.
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MeSH Terms
3T3 Cells
Cell Differentiation / drug effects
Cell Division / drug effects
Cell Line
Dimethyl Sulfoxide / pharmacology
Enzyme Activation
Heme / physiology*
Hemoglobins / biosynthesis*
Leukemia, Erythroblastic, Acute
Recombinant Proteins / metabolism
Tumor Cells, Cultured
eIF-2 Kinase / metabolism*
Grant Support
Reg. No./Substance:
0/Hemoglobins; 0/Recombinant Proteins; 14875-96-8/Heme; 67-68-5/Dimethyl Sulfoxide; EC Kinase

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