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Molecular and Cellular Biology, August 2000, p. 6084-6094, Vol. 20, No. 16
The Center for Blood Research and Harvard
Medical School1 and The Harvard School
of Public Health,3 Boston, Massachusetts
02115; Department of Molecular and Cellular Biology, Harvard
University, Cambridge, Massachusetts 021382;
and Pulmonary Center, Boston University School of Medicine,
Boston, Massachusetts 021184
Received 10 May 2000/Accepted 19 May 2000
The tumor necrosis factor alpha (TNF-
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
A Lipopolysaccharide-Specific Enhancer Complex Involving Ets,
Elk-1, Sp1, and CREB Binding Protein and p300 Is Recruited to the
Tumor Necrosis Factor Alpha Promoter In Vivo
) gene is rapidly activated
by lipopolysaccharide (LPS). Here, we show that extracellular signal-regulated kinase (ERK) kinase activity but not calcineurin phosphatase activity is required for LPS-stimulated TNF-
gene expression. In LPS-stimulated macrophages, the ERK substrates Ets and
Elk-1 bind to the TNF-
promoter in vivo. Strikingly, Ets and Elk-1
bind to two TNF-
nuclear factor of activated T cells (NFAT)-binding
sites, which are required for calcineurin and NFAT-dependent TNF-
gene expression in lymphocytes. The transcription factors ATF-2, c-jun,
Egr-1, and Sp1 are also inducibly recruited to the TNF-
promoter in
vivo, and the binding sites for each of these activators are required
for LPS-stimulated TNF-
gene expression. Furthermore, assembly of
the LPS-stimulated TNF-
enhancer complex is dependent upon the
coactivator proteins CREB binding protein and p300. The finding that a
distinct set of transcription factors associates with a fixed set of
binding sites on the TNF-
promoter in response to LPS stimulation
lends new insights into the mechanisms by which complex patterns of
gene regulation are achieved.
*
Corresponding author. Mailing address: The Center for
Blood Research and Harvard Medical School, 800 Huntington Ave.,
Boston, MA 02115. Phone: (617) 278-3351. Fax: (617) 278-3454. E-mail: goldfeld{at}cbr.med.harvard.edu.
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