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Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1567-1578
Role of Cytokine Signaling Molecules in Erythroid Differentiation of
Mouse Fetal Liver Hematopoietic Cells: Functional Analysis of Signaling
Molecules by Retrovirus-Mediated Expression
Dai Chida,
Osamu Miura,
Akihiko Yoshimura, and
Atsushi Miyajima
From the Institute of Molecular and Cellular Biosciences, The
University of Tokyo; the First Department of Internal Medicine, Tokyo
Medical and Dental University; and Institute of Life Science, Kurume
University, Kurume, Japan.
Erythropoietin (EPO) and its cell surface receptor (EPOR) play a
central role in proliferation, differentiation, and survival of
erythroid progenitors. Signals induced by EPO have been studied extensively by using erythroid as well as nonerythroid cell lines, and
various controversial results have been reported as to the role of
signaling molecules in erythroid differentiation. Here we describe a
novel approach to analyze the EPO signaling by using primary mouse
fetal liver hematopoietic cells to avoid possible artifacts due to
established cell lines. Our strategy is based on high-titer retrovirus
vectors with a bicistronic expression system consisting of an internal
ribosome entry site (IRES) and green fluorescent protein (GFP). By
placing the cDNA for a signaling molecule in front of IRES-GFP,
virus-infected cells can be viably sorted by fluorescence-activated
cell sorter, and the effect of expression of the signaling molecule can
be assessed. By using this system, expression of cell-survival genes
such as Bcl-2 and Bcl-XL was found to enhance erythroid colony
formation from colony-forming unit-erythroid (CFU-E) in
response to EPO. However, their expression was not sufficient for
erythroid colony formation from CFU-E alone, indicating that EPO
induces signals for erythroid differentiation. To examine the role of
EPOR tyrosine residues in erythroid differentiation, we introduced a
chimeric EGFR-EPOR receptor, which has the extracellular domain of the
EGF receptor and the intracellular domain of the EPOR, as well as a
mutant EGFR-EPOR in which all the cytoplasmic tyrosine residues are
replaced with phenylalanine, and found that tyrosine residues of EPOR
are essential for erythroid colony formation from CFU-E. We further
analyzed the function of the downstream signaling molecules by
expressing modified signaling molecules and found that both JAK2/STAT5
and Ras, two major signaling pathways activated by EPOR, are involved
in full erythroid differentiation.
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