Targeting combinatorial transcriptional complex assembly at specific modules within the interleukin-2 promoter by the immunosuppressant SB203580.
J Biol Chem
; 278(42): 41034-46, 2003 Oct 17.
Article
em En
| MEDLINE
| ID: mdl-12896977
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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Base de dados:
MEDLINE
Assunto principal:
Transcrição Gênica
Idioma:
En
Ano de publicação:
2003
Tipo de documento:
Article