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Transforming growth factor-beta relieves stem cell factor-induced
proliferation of myelogenous leukemia cells through inhibition of binding
of the transcription factor NF-jun
C Sott, B Dorner, L Karawajew, F Herrmann and MA Brach
Department of Medical Oncology and Applied Molecular Biology, Freie
Universitat Berlin, Universitatsklinikum Rudolf Virchow, Germany.
Transforming growth factor-beta (TGF-beta) is a potent inhibitor of growth
factor-stimulated hematopoiesis in normal and leukemic conditions. Using
the factor-dependent myelogenous leukemia cell lines GF-D8 and Mo7, we show
that TGF-beta interferes with stem cell factor (SCF)-induced proliferation
by downmodulating c-jun gene expression. The ability of SCF to induce
accumulation of c-jun transcripts was abolished when TGF-beta was present
in culture. Transcriptional nuclear run-on assays indicated that TGF-beta
relieved the capacity of SCF to enhance the transcriptional rate of the
c-jun gene. Deletion analysis of the c-jun promoter furthermore showed that
SCF was activating the c- jun promoter via the NF-jun transcription factor.
Gel mobility shift assays showed that SCF increased the binding activity of
NF-jun to its recognition site within 5 to 15 minutes. Binding activity
peaked at 1 hour after exposure to SCF and declined to starting levels
within 4 hours. The ability of SCF to enhance NF-jun binding activity was
also dose-dependent in the range of 5 to 100 ng/mL. Exposure of GF-D8 and
Mo7 cells to TGF-beta before the addition of SCF antagonized SCF- induced
NF-jun binding. Moreover, whereas SCF was capable of functionally
activating a heterologous promoter containing the NF-jun binding site,
pretreatment of GF-D8 cells with TGF-beta abolished transcriptional
activation of this heterologous promoter. These findings indicate that
SCF-mediated activation of c-jun via NF-jun is crucial for the
SCF-inducible proliferative response and is inhibited by TGF-beta. In
additional experiments, the antisense technique was used. Treatment of
GF-D8 and Mo7 cells with an antisense oligodeoxyribonucleotide directed
against the translation initiation site of c-jun abolished the capacity of
SCF to induce a proliferative response, whereas sense and nonsense
oligomers had no effect. Taken together, our data indicate that the
counteracting modulation of the binding activity of NF-jun by SCF and
TGF-beta regulates the expression of the c-jun gene and thereby the
proliferative state of the GF-D8 and Mo7 target.
Volume 84,
Issue 6,
pp. 1950-1959,
09/15/1994
Copyright © 1994 by The American Society of Hematology
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