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Blood, 1 November 2000, Vol. 96, No. 9, pp. 3241-3248
RED CELLS
Regulation of hemoglobin synthesis and proliferation of
differentiating erythroid cells by heme-regulated
eIF-2 kinase
John S. Crosby,
Peter J. Chefalo,
Irene Yeh,
Shong Ying,
Irving M. London,
Philippe Leboulch, and
Jane-Jane Chen
From the Harvard-Massachusetts Institute of Technology
Division of Health Sciences and Technology and the Department of
Biology, Massachusetts Institute of Technology, Cambridge MA;
Harvard Medical School, Hematology Division, Department of Medicine,
Brigham and Women's Hospital, Boston, MA.
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-2
kinase (HRI), which blocks the initiation of protein synthesis by
phosphorylating eIF-2. 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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