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Transforming growth factor beta 1 inhibits expression of the gene products
for steel factor and its receptor (c-kit)
MC Heinrich, DC Dooley and WW Keeble
Department of Medicine, Oregon Health Sciences University, Portland, USA.
Transforming growth factor beta 1 (TGF-beta 1), a product of marrow stromal
cells, inhibits the proliferation and differentiation of hematopoietic
progenitor cells within the hematopoietic microenvironment. Steel factor
(SF), also a product of marrow stromal cells, is an essential positive
regulator of hematopoiesis in vivo. TGF- beta 1 has been shown to repress
human and murine leukemic cell and murine lin- bone marrow mononuclear cell
expression of the receptor for SF (c-kit). We speculated that TGF-beta 1
might exert its inhibitory effect on hematopoiesis in part by decreasing
SF/c-kit interactions. Therefore, we tested the hypothesis that TGF-beta 1
inhibits both stromal cell expression of SF and hematopoietic progenitor
cell expression of c-kit. We measured stromal cell expression of SF protein
and hematopoietic progenitor cell expression of membrane-bound c-kit before
and after exposure to recombinant human TGF-beta 1. Both stromal cell
expression of SF protein and hematopoietic progenitor cell expression of
c-kit protein were inhibited 50% to 80% by TGF-beta 1. Using Northern blot
and ribonuclease protection assays, we determined that TGF-beta 1 repressed
stromal cell SF mRNA, but did not alter SF transcript stability. TGF-beta 1
was also found to repress c-kit mRNA in human leukemic myeloblasts as well
as in normal lin- hematopoietic progenitor cells. In contrast with its
effect on SF mRNA, TGF-beta 1 accelerated the degradation of c-kit mRNA. We
conclude that TGF-beta 1 inhibits stromal cell production of SF by
repression of SF gene transcription and represses hematopoietic progenitor
cell expression of c-kit by decreasing the stability of c-kit transcripts.
Taking into account the importance of SF and c-kit in maintaining
steady-state hematopoiesis in vivo, the dual effect of TGF-beta 1 on both
SF and c- kit gene expression is likely to be one of the major mechanisms
by which TGF-beta 1 inhibits hematopoiesis in vivo.
Volume 85,
Issue 7,
pp. 1769-1780,
04/01/1995
Copyright © 1995 by The American Society of Hematology
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