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A Novel Function of Stat1 and Stat3 Proteins in
Erythropoietin-Induced Erythroid Differentiation of a Human Leukemia
Cell Line
Keita Kirito,
Mie Uchida,
Masaaki Takatoku,
Koichi Nakajima,
Toshio Hirano,
Yasusada Miura, and
Norio Komatsu
From the Division of Hematology, Department of Medicine, Jichi
Medical School, Tochigi, Japan; and the Department of Molecular
Oncology, Biomedical Research Center, Osaka University Medical School,
Osaka, Japan.
We recently determined that erythropoietin (EPO) activates 3 members
of the signal transducer and activator of transcription (STAT) family,
Stat1 , Stat3, and Stat5, in the human EPO-dependent cell lines, UT-7
and UT-7/EPO (Kirito et al, J Biol Chem 272:16507, 1997). In
addition, we have shown that Stat1, but not Stat3, is involved in
EPO-induced cellular proliferation. In this study, we examined the
roles of Stat1 and Stat3 in EPO-induced erythroid differentiation.
UT-7/GM was used as a model system, because this cell line can
differentiate into erythroid-lineage cells with EPO treatment (Komatsu
et al, Blood 89:4021, 1997). We found that EPO did not activate
Stat1 or Stat3 in UT-7/GM cells. Transfection experiments showed
that both Stat1 and Stat3 inhibited the induction by EPO of
 -globin and erythroid-specific 5-aminolevulinate synthetase transcripts, resulting in a reduction of the percentage of
hemoglobin-positive cells. Dominant negative forms of Stat1 or Stat3
promoted the EPO-induced erythroid differentiation of UT-7/GM cells,
even in the presence of granulocyte-macrophage colony-stimulating
factor, although this cytokine never induced erythroid differentiation of the parent UT-7/GM cells with or without EPO. A cell cycle analysis
showed that the constitutive activation of Stat1, but not Stat3,
shortened the period of G0/G1 prolongation caused by EPO stimulation.
Taken together, our data suggest that Stat1 and Stat3 act as
negative regulators in EPO-induced erythroid differentiation.
Specifically, Stat1 may activate a cell cycle-associated gene(s),
leading to the entry of cells into the cell cycle.
Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 462-471
© 1998 by the American Society of Hematology.
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