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(Received for publication, January 12, 1996, and in revised form, March 8, 1996)
From the Division of Human Immunology, Hanson Centre for Cancer
Research, Institute of Medical and Veterinary Science, Frome Road,
Adelaide 5000, South Australia, Australia
Granulocyte-macrophage colony-stimulating factor
(GM-CSF) is a hemopoietic growth factor that is expressed in activated
T cells, fibroblasts, macrophages, and endothelial cells. Although
GM-CSF does not appear to be essential for normal hemopoiesis,
overexpression of GM-CSF has been implicated in the pathogenesis of
some diseases such as myeloid leukemia and chronic inflammation. An
NF-
Volume 271, Number 24,
Issue of June 14, 1996
pp. 14438-14444
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
B/Rel binding site within the GM-CSF promoter, termed the B
element appears to be important for controlling expression in reporter
gene assays in response to a number of stimuli in T cells. We
investigated oligonucleotide-directed triple helix formation across
this regulatory sequence as a potential tool to inhibit GM-CSF gene
transcription. A 15-base oligonucleotide, GM3, was targeted to a
purine-rich region in the GM-CSF proximal promoter, which overlaps the
B element. Gel mobility shift assays and DNase I footprinting
demonstrated that GM3 formed a sequence-specific collinear triplex with
its double-stranded DNA target. Triplex formation by GM3 blocked
recombinant and nuclear NF-B proteins binding to the GM-CSF element.
GM3 also caused selective inhibition of the human T-cell lymphotrophic
virus-1 Tax transactivator-induced luciferase activity from a reporter
construct driven by the GM-CSF promoter in Jurkat T cells. Finally, GM3
greatly reduced the concentration of endogenous GM-CSF mRNA induced
by different stimuli in Jurkat T cells but did not affect interleukin 3 mRNA levels in the same cells. We conclude that the B element in
the GM-CSF promoter plays a central role in the transcriptional
activation of the endogenous GM-CSF gene. Colinear triplex formation
acts as a selective transcriptional repressor of the GM-CSF gene and
may have potential therapeutic application in cases of undesirable
overexpression of this protein.
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