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B Transcription Factor c-Rel1
* Division of Molecular Bioscience and
Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, Canberra, Australia;
School of Molecular and Microbial Biosciences, University of Sydney, Sydney, Australia; and
Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
It is well established that the NF-
B family of transcription factors serves a major role in controlling gene expression in response to T cell activation, but the genome-wide roles of individual family members remain to be determined. c-Rel, a member of the NF-B family, appears to play a specific role in T cell function because T cells from c-Rel–/– animals are defective in their response to immune signals. We have used expression profiling to identify sets of genes that are affected by either deletion or overexpression of c-Rel in T cells. Very few of these genes exhibit a strong requirement for c-Rel; rather, c-Rel appears to modulate the expression of a large number of genes in these cells. The sets of c-Rel-affected genes are significantly enriched for genes containing consensus NF-B/Rel sites in their proximal promoter regions. In addition, their promoters contain a higher average density of NF-B/Rel sites compared with all genes represented on the microarrays. A transcriptional module comprised of two closely spaced c-Rel consensus sites is found with higher frequency in the c-Rel-affected gene sets and may represent an important control module for genes regulated by c-Rel or other NF-B family members. We confirmed the importance of these findings on a subgroup of genes by using quantitative PCR to monitor gene expression as well as in vitro c-Rel/DNA binding assays and luciferase reporter assays. The c-Rel-regulated genes identified here support a role for c-Rel in inflammatory responses as well as in the promotion of cell growth and survival.
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.
1 This work is supported by grants from the National Health and Medical Research Council of Australia and Diabetes Australia (to M.F.S.) and an Australian Postgraduate Award Ph.D. scholarship received by K.B.
2 Address correspondence and reprint requests to Dr. M. Frances Shannon, Division of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, Canberra, Australia. E-mail address: frances.shannon{at}anu.edu.au
3 Abbreviations used in this paper: wt, wild type; CD28RE, CD28 responsive element; IRES, internal ribosome entry site; KO, knockout; NS, nonstimulated; P/I, PMA/ionomycin; QPCR, quantitative PCR; TFBS, transcription factor binding site; TSS, transcription start site; UBC, ubiquitin-conjugating enzyme.
4 The online version of this article contains supplemental material.
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