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J. Biol. Chem., Vol. 280, Issue 17, 17435-17448, April 29, 2005
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Identification of Direct Genomic Targets Downstream of the Nuclear Factor-
B Transcription Factor Mediating Tumor Necrosis Factor Signaling*
¶||
From the
Department of Medicine and the ¶Sealy Center for Molecular Science, The University of Texas Medical Branch, Galveston, Texas 77555-1060
Tumor necrosis factor (TNF) is a pro-inflammatory cytokine that controls expression of inflammatory genetic networks. Although the nuclear factor-
B (NF-B) pathway is crucial for mediating cellular TNF responses, the complete spectrum of NF-B-dependent genes is unknown. In this study, we used a tetracycline-regulated cell line expressing an NF-B inhibitor to systematically identify NF-B-dependent genes. A microarray data set generated from a time course of TNF stimulation in the presence or absence of NF-B signaling was analyzed. We identified 50 unique genes that were regulated by TNF (Pr(F) <0.001) and demonstrated a change in signal intensity of ± 3-fold relative to control. Of these, 28 were NF-B-dependent, encoding proteins involved in diverse cellular activities. Quantitative real-time PCR assays of eight characterized NF-B-dependent genes and five genes not previously known to be NF-B-dependent (Gro-
and-
, IB
, interleukin (IL)-7R, and Naf-1) were used to determine whether they were directly or indirectly NF-B regulated. Expression of constitutively active enhanced green fluorescent·NF-B/Rel A fusion protein transactivated all but IL-6 and IL-7R in the absence of TNF stimulation. Moreover, TNF strongly induced all 12 genes in the absence of new protein synthesis. High probability NF-B sites in novel genes were predicted by binding site analysis and confirmed by electrophoretic mobility shift assay. Chromatin immunoprecipitation assays show the endogenous IB
/, Gro-/, and Naf-1 promoters directly bound NF-B/Rel A in TNF-stimulated cells. Together, these studies systematically identify the direct NF-B-dependent gene network downstream of TNF signaling, extending our knowledge of biological processes regulated by this pathway.
Received for publication, January 13, 2005 , and in revised form, February 16, 2005.
* This work was supported in part by NIAID, National Institutes of Health Grant R01 AI40218 (to A. R. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Supported by a predoctoral fellowship from the J. W. McLaughlin Foundation.
|| To whom correspondence should be addressed: Division of Endocrinology, MRB 8.138, The University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1060. Tel.: 409-772-2824; Fax: 409-772-8709; E-mail: arbrasie{at}utmb.edu.
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