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J. Biol. Chem., Vol. 277, Issue 7, 4981-4988, February 15, 2002
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From the Tumor necrosis factor-
A High Affinity HSF-1 Binding Site in the 5'-Untranslated Region
of the Murine Tumor Necrosis Factor-
Gene Is a Transcriptional
Repressor*
§,,
**
Department of Medicine, Division of
Pulmonary and Critical Care Medicine, and the
Departments of Biochemistry and Molecular Biology and
Pathology, University of Maryland School of Medicine, the
** University of Maryland Biopolymer Cytokine Core
Laboratory, and the Medical and Research Services of the Baltimore
Veterans Administration Medical Center, Baltimore, Maryland 21201 and
the ¶ Dana Farber Cancer Institute and Joint Center for Radiation
Therapy, Harvard Medical School, Boston, Massachusetts 02115
(TNF) is
a pivotal early mediator of host defenses that is essential for
survival in infections. We previously reported that exposing
macrophages to febrile range temperatures (FRT) (38.5-40 °C)
markedly attenuates TNF expression by causing abrupt and premature
cessation of transcription. We showed that this inhibitory effect of
FRT is mediated by an alternatively activated repressor form of heat
shock factor 1 (HSF-1) and that a fragment of the TNF
gene comprising a minimal 85-nucleotide (nt) proximal promoter and the
138-nt 5'-untranslated region (UTR) was sufficient for mediating this
effect. In the present study we have used an electrophoretic mobility
shift assay (EMSA) to identify a high affinity binding site for HSF-1
in the 5'-UTR of the TNF gene and have used a chromosome
immunoprecipitation assay to show that HSF-1 binds to this region of
the endogenous TNF gene. Mutational inactivation of this
site blocks the inhibitory effect of overexpressed HSF-1 on activity of
the minimal TNF promoter (
85/+138) in Raw 264.7 murine
macrophages, identifying this site as an HSF-1-dependent
repressor. However, the same mutation fails to block repression of a
full-length (1080/+138) TNF promoter construct by
HSF-1 overexpression, and HSF-1 binds to upstream sequences in the
regions 1080/845, 533/196, and 326/39 nt in EMSA,
suggesting that additional HSF-1-dependent repressor elements are present upstream of the minimal 85-nt promoter. Furthermore, although mutation of the HSF-1 binding site in the minimal
TNF promoter construct abrogates HSF-1-mediated
repression, the same mutation fails to abrogate repression of this
construct by high levels of HSF-1 overexpression or exposure to
39.5 °C. This suggests that HSF-1 might repress TNF transcription
through redundant mechanisms, some of which might not require high
affinity binding of HSF-1.
*
This work was supported by Veterans Administration Merit
Review Grant 128444285-0005 (to J. D. H.), the Passano Foundation (to J. D. H.), United States Public Health Services Grant AI42117 (to
J. D. H.), and a grant from the Baltimore Research and Education Foundation (to I. S. S.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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