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J. Biol. Chem., Vol. 278, Issue 42, 41034-41046, October 17, 2003

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Targeting Combinatorial Transcriptional Complex Assembly at Specific Modules within the Interleukin-2 Promoter by the Immunosuppressant SB203580^*,

James L. Smith, Irene Collins, G. V. R. Chandramouli, Wayne G. Butscher, Elena Zaitseva, Wendy J. Freebern, Cynthia M. Haggerty, Victoria Doseeva and Kevin Gardner 

From the Advanced Technology Center, Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health, Bethesda, Maryland 20892-4605

The proximal promoter sequence of the interleukin-2 (IL-2) gene contains a series of composite sites or modules that controls much of its responsiveness to environmental stimuli. The integrated targeting of these modules is therefore a major mode of regulation. This report describes how multiple functional hierarchies, required for the recruitment of the p300 co-activator to the CD28RE/AP1 (TRE) module of the IL-2 promoter, are selectively disrupted in human T-cells by the immunosuppressive and anti-inflammatory actions of the p38 mitogen-activated protein kinase inhibitor (MAPK), SB203580. The molecular hierarchies targeted by SB203580 include the combinatorial interaction of NF-B and CREB at the CD28RE/AP1 element coupled with the subsequent dynamic co-assembly and activation of p300. Several aspects of this targeting are linked to the ability of SB203580 to inhibit p38 MAPK-controlled pathways. Together, these results provide the molecular basis through which the combinatorial structure and context of the composite elements of the IL-2 promoter dictates mitogen responsiveness and drug susceptibility that are quantitatively and qualitatively distinct from the isolated action of single consensus sequences and/or transcriptional motifs.

Received for publication, May 29, 2003 , and in revised form, July 30, 2003.

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–4.

To whom correspondence should be addressed: National Institutes of Health, Advanced Technology Center, Rm. 134C, 8717 Grovemont Circle, Bethesda, MD 20892-4605. Tel: 301-496-1055; Fax: 301-435-7558; E-mail: gardnerk{at}mail.nih.gov.

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