Rothenberg, Ellen V. and Ward, Susan B. (1996) A dynamic assembly of diverse transcription factors integrates activation and cell-type information for interleukin 2 gene regulation. Proceedings of the National Academy of Sciences of the United States of America, 93 (18). pp. 9358-9365. ISSN 0027-8424 http://resolver.caltech.edu/CaltechAUTHORS:ROTpnas96
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The interleukin 2 (IL-2) gene is subject to two types of regulation: its expression is T-lymphocyte-specific and it is acutely dependent on specific activation signals. The IL-2 transcriptional apparatus integrates multiple types of biochemical information in determining whether or not the gene mill be expressed, using multiple diverse transcription factors that are each optimally activated or inhibited by different signaling pathways. When activation of one or two of these factors is blocked, IL-2 expression is completely inhibited. The inability of the other, unaffected factors to work is explained by the striking finding that none of the factors interacts stably with its target site in the IL-2 enhancer unless all the factors are present. Coordinate occupancy of all the sites in the minimal enhancer is apparently maintained by continuous assembly and disassembly cycles that respond to the instantaneous levels of each factor in the nuclear compartment. In addition, the minimal enhancer undergoes specific increases in DNase I accessibility, consistent with dramatic changes in chromatin structure upon activation. Still to be resolved is what interaction(s) conveys T-lineage specificity. In the absence of activating signals, the minimal IL-2 enhancer region in mature T cells is apparently unoccupied, exactly as in non-T lineage cells. However, in a conserved but poorly studied upstream region, we have now mapped several novel sites of DNase I hypersensitivity in vivo that constitutively distinguish IL-2 producer type T cells from cell types that cannot express IL-2. Thus a distinct domain of the IL-2 regulatory sequence may contain sites for competence- or lineage-marking protein contacts.
|Additional Information:||Copyright © 1996 by the National Academy of Sciences. This paper was presented at a colloquium entitled "Biology of Developmental Transcription Control," organized by Eric H. Davidson, Roy J. Britten, and Gary Felsenfeld, held October 26-28, 1995, at the National Academy of Sciences in Irvine, CA. We wish to thank Drs. Edgar Serfling and Mark Brunvand for communication of valuable work prior to publication, Eric Davidson and Michael Levine for challenging discussion and stimulating criticism, and Dan Chen, Paul Garrity, Paul Mueller, and Barbara Wold for continuing interest and advice. We thank the members of the Rothenberg laboratory for support, and James Staub and Richard Gomez for careful help with the photography. This work was supported by grants from the Public Health Service (AI34041 and AG13108) and from the State of California Tobacco-Related Disease Research Program, and aided by a donation from the Golden West Co. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.|
|Subject Keywords:||T lymphocytes, in vivo footprinting, NF-AT, NF-kappa B, AP-1, accessory molecule CD28, locus-control region, primary T-cells, IL-2 gene, nuclear factor, lymphocytes-T, cyclosporine-A, in-vivo, glucocorticoid receptor|
|Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Tony Diaz|
|Deposited On:||17 Nov 2005|
|Last Modified:||26 Dec 2012 08:42|
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