Targeting combinatorial transcriptional complex assembly at specific modules within the interleukin-2 promoter by immunosuppressant SB203580
Authors:
Smith JL, Collins I, Chandramouli GVR, Butscher WG, Zaitseva E, Freebern WJ, Haggerty CM, Doseeva V and Gardner K
In:
Source:
J Biol Chem
Publication Date:
(
2003
)
Issue:
278(42)
:
41034-41046
Research Area:
Immunotherapy / Hematology
Cells used in publication:
T cell, human peripheral blood unstim.
Species: human
Tissue Origin: blood
Experiment
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. This publication 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 immuno-suppressive and anti-inflammatory actions of p38 mitogen-activated protein kinase inhibitor (MAPK), SB203580. Primary human T cells were transfected with luciferase reporter plasmid encoding either wild type or mutated CD28RE/AP1 promoter element. Cells were co-nucleofected with a p38 MAPK expression vector. Overexpression of p38 MAPK lead to a significant transactivation of the CD28RE/AP1 (TRE) element.
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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