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Blood, Vol. 93 No. 3 (February 1), 1999:
pp. 816-825
Prolonged Expression of c-fos Suppresses Cell Cycle Entry of
Dormant Hematopoietic Stem Cells
Seiji Okada,
Tetsuya Fukuda,
Kunimasa Inada, and
Takeshi Tokuhisa
From the Department of Developmental Genetics, Chiba University
Graduate School of Medicine, Chiba, Japan.
The proto-oncogene c-fos was transiently upregulated in
primitive hematopoietic stem (Lin Sca-1+)
cells stimulated with stem cell factor, interleukin-3 (IL-3), and IL-6.
To investigate a role of the c-fos in hematopoietic stem cells,
we used bone marrow (BM) cells from transgenic mice carrying the
c-fos gene under the control of the
interferon- / -inducible Mx-promoter (Mx-c-fos), and fetal liver
cells from c-fos-deficient mice. Prolonged expression of the
c-fos in LinSca-1+ BM cells
inhibited factor-dependent colony formation and hematopoiesis on a
stromal cell layer by keeping them at G0/G1 phase of the cell cycle.
These LinSca-1+ BM cells on a stromal
layer entered into the cell cycle whenever exogenous c-fos was
downregulated. However, ectopic c-fos did not perturb colony
formation by LinSca-1+ BM cells after they
entered the cell cycle. Furthermore, endogenous c-fos is not
essential to cell cycle progression of hematopoietic stem cells because
the factor-dependent and the stroma-dependent hematopoiesis by
LinSca-1+ fetal liver cells from
c-fos-deficient mice was not impaired. These results suggest
that the c-fos induced in primitive hematopoietic stem cells
negatively controls cell cycle progression and maintains them in a
dormant state.
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