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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·Kevin Gardner
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Abstract

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-kappaB 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.

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Amino Acid MotifsBase SequenceCell LineCell NucleusDose-Response Relationship, DrugEnzyme InhibitorsHumansImidazolesInterleukin-2Jurkat CellsMAP Kinase Signaling SystemMitogen-Activated Protein KinasesModels, StatisticalMolecular Sequence DataPhosphorylationPlasmidsPrecipitin TestsPromoter Regions, GeneticPyridinesSignal TransductionT-LymphocytesTime FactorsTranscription, GeneticTranscriptional ActivationTransfectionp38 Mitogen-Activated Protein KinasesJournal Article

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James L Smith, Irene Collins, G V R Chandramouli, Wayne G Butscher, Elena Zaitseva, Wendy J Freebern, Cynthia M Haggerty, Victoria Doseeva, Kevin Gardner. 2003-08-01. Targeting combinatorial transcriptional complex assembly at specific modules within the interleukin-2 promoter by the immunosuppressant SB203580.. https://doi.org/10.1074/jbc.m305615200

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