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Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 941-949
A member of Forkhead family transcription factor, FKHRL1, is one
of the downstream molecules of phosphatidylinositol 3-kinase-Akt
activation pathway in erythropoietin signal transduction
Yoshifumi Kashii,
Mie Uchida,
Keita Kirito,
Masaru Tanaka,
Kousuke Nishijima,
Masaki Toshima,
Tomoko Ando,
Kazuki Koizumi,
Tomoyuki Endoh,
Ken-ichi Sawada,
Mariko Momoi,
Yasusada Miura,
Keiya Ozawa, and
Norio Komatsu
From the Departments of Pediatrics and Hematology, Jichi Medical
School, Tochigi, Japan; Department of Internal Medicine II, Hokkaido
University School of Medicine, Sapporo, Japan.
The phosphatidylinositol 3-kinase (PI3K) signaling pathway is
important for the regulation of a number of cellular responses. Serine/threonine kinase Akt (protein kinase B; PKB) is downstream of
PI3K and activated by growth factors. This study found that erythropoietin (EPO) induced tyrosine phosphorylation of Akt in a time-
and dose-dependent manner in EPO-dependent human leukemia cell line
UT-7/EPO. In vitro kinase assay using histone H2B and glucose synthase
kinase as substrates demonstrated that Akt was actually activated by
EPO. EPO-induced phosphorylation of Akt was completely blocked by a
PI3K-specific inhibitor, LY294002, at 10 µmol/L, indicating that
activation of Akt by EPO is dependent on PI3K activity. In addition,
overexpression of the constitutively active form of Akt on UT-7/EPO
cells partially blocked apoptosis induced by withdrawal of EPO from the
culture medium. This finding suggested that the PI3K-Akt activation
pathway plays some role in the antiapoptotic effect of EPO. EPO induced
phosphorylation of a member of the trancription factor Forkhead family,
FKHRL1, at threonine 32 and serine 253 in a dose- and time-dependent
manner in UT-7/EPO cells. Moreover, results showed that Akt kinase
activated by EPO directly phosphorylated FKHRL1 protein and that FKHRL1 phosphorylation was completely dependent on PI3K activity as is the
case for Akt. In conjunction with the evidence that FKHRL1 is expressed
in normal human erythroid progenitor cells and erythroblasts, the
results suggest that FKHRL1 plays an important role in erythropoiesis as one of the downstream target molecules of PI3K-Akt.
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