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Blood, 15 October 2002, Vol. 100, No. 8, pp. 2753-2762
HEMATOPOIESIS
Activation of the Jak3 pathway is associated with granulocytic
differentiation of myeloid precursor cells
Sushil G. Rane,
James K. Mangan,
Arshad Amanullah,
Brian C. Wong,
Renu K. Vora,
Dan A. Liebermann,
Barbara Hoffman,
Xavier Graña, and
E. Premkumar Reddy
From the Department of Biochemistry and Fels Institute
for Cancer Research and Molecular Biology, Temple University School of
Medicine, Philadelphia, PA.
Jak3, a member of the Janus kinase family of cytoplasmic tyrosine
kinases, is expressed at low levels in immature hematopoietic cells and
its expression is dramatically up-regulated during the terminal
differentiation of these cells. To better understand the role of Jak3
in myeloid cell development, we have investigated the role of Jak3 in
myeloid cell differentiation using the 32Dcl3 cell system. Our studies
show that Jak3 is a primary response gene for
granulocyte colony-stimulating factor (G-CSF) and the accumulation of
tyrosine phosphorylated Jak3 correlated with cell growth inhibition and
terminal granulocytic differentiation in response to G-CSF. Ectopic
overexpression of Jak3 in 32Dcl3 cells resulted in an acceleration of
the G-CSF-induced differentiation program that was preceded by
G1 cell cycle arrest, which was associated with the
up-regulation of the cyclin-dependent kinase inhibitor p27Kip1 and down-regulation of Cdk2, Cdk4, Cdk6,
and Cyclin E. In addition, ectopic overexpression of Jak3 appears
to result in the inactivation of PKB/Akt and Stat3-mediated
proliferative pathways in the presence of G-CSF. Similarly,
overexpression of Jak3 in primary bone marrow cells resulted in an
acceleration of granulocytic differentiation in the presence of
granulocyte-macrophage colony-stimulating factor, which was associated
with their growth arrest in the G1 phase of the cell cycle.
Taken together, these results indicate that Jak3-mediated signals play
an important role in myeloid cell differentiation.
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