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Molecular and Cellular Biology, December 2001, p. 7971-7980, Vol. 21, No. 23
Harvard-MIT Division of Health Sciences and
Technology, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139
Received 4 May 2001/Returned for modification 6 June 2001/Accepted 27 August 2001
Cytoplasmic stresses, including heat shock, osmotic stress, and
oxidative stress, cause rapid inhibition of protein synthesis in cells
through phosphorylation of eukaryotic initiation factor 2
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.23.7971-7980.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Translation Initiation Control by
Heme-Regulated Eukaryotic Initiation Factor 2
Kinase in
Erythroid Cells under Cytoplasmic Stresses

(eIF2
)
by eIF2
kinases. We have investigated the role of heme-regulated
inhibitor (HRI), a heme-regulated eIF2
kinase, in stress
responses of erythroid cells. We have demonstrated that HRI in
reticulocytes and fetal liver nucleated erythroid progenitors is
activated by oxidative stress induced by arsenite, heat shock, and
osmotic stress but not by endoplasmic reticulum stress or nutrient
starvation. While autophosphorylation is essential for the activation
of HRI, the phosphorylation status of HRI activated by different
stresses is different. The contributions of HRI in various stress
responses were assessed with the aid of HRI-null reticulocytes
and fetal liver erythroid cells. HRI is the only eIF2
kinase
activated by arsenite in erythroid cells, since HRI-null cells do not
induce eIF2
phosphorylation upon arsenite treatment. HRI is also the
major eIF2
kinase responsible for the increased eIF2
phosphorylation upon heat shock in erythroid cells. Activation of HRI
by these stresses is independent of heme and requires the presence of
intact cells. Both hsp90 and hsc70 are necessary for all stress-induced
HRI activation. However, reactive oxygen species are involved only in
HRI activation by arsenite. Our results provide evidence for a novel
function of HRI in stress responses other than heme deficiency.
*
Corresponding author. Mailing address: E25-545,
Massachusetts Institute of Technology, 77 Massachusetts Ave.,
Cambridge, MA 02139. Phone: (617) 253-9674. Fax: (617) 253-3459. E-mail: j-jchen{at}mit.edu.
Present address: Department of Cancer Immunology and AIDS,
Dana-Farber Cancer Institute, Boston, MA 02115.
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