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Transforming growth factor-beta regulates c-kit message stability and
cell-surface protein expression in hematopoietic progenitors
CM Dubois, FW Ruscetti, J Stankova and JR Keller
Faculty of Medicine, Department of Pediatrics, University of Sherbrooke,
Quebec, Canada.
The cell-surface receptor c-kit and its cognate ligand stem-cell factor
(SCF) or steel factor (SLF) are important for the maintenance of
hematopoiesis both in vitro and in vivo. Transforming growth factor- beta
(TGF-beta) has been shown to be a potent inhibitor of SLF-mediated
synergistic growth of murine Lin-Sca-1+ progenitor cells, as well as more
committed progenitors. In the present study, we examined the regulation of
c-kit mRNA and cell-surface expression by TGF-beta. Among the murine
hematopoietic progenitor cells tested, the myeloid cell line FDC-P1 and the
mast-cell line MC-6, as well as progenitor-enriched bone marrow cells,
constitutively expressed functional cell-surface c-kit. Treatment of these
progenitor cell lines and primary progenitor cells with TGF-beta resulted
in downregulation of cell-surface c-kit expression. This effect was not a
secondary event of cell-cycle status. TGF-beta inhibition was dose- and
time-dependent, with 50% inhibition seen between 0.3 to 3 ng/mL TGF-beta
and maximal inhibition at 30 ng/mL. Using the FDC-P1 cell line, we observed
that the inhibition of cell-surface c-kit expression by TGF-beta is
preceded by a marked reduction in c-kit mRNA levels starting 2 hours after
TGF-beta treatment, and reaches a maximum by 6 hours. The inhibition in
steady- state c-kit mRNA levels is explained, in part, by a decrease in the
half-life of c-kit transcripts (2 to 4 hours for control cells v 0.5 to 1.5
hours for TGF-beta-treated cells). These findings suggest that TGF- beta
regulates the responsiveness of murine hematopoietic progenitors to SLF
through a decrease in c-kit message stability leading to decreased
cell-surface expression.
Volume 83,
Issue 11,
pp. 3138-3145,
06/01/1994
Copyright © 1994 by The American Society of Hematology
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