Targeting combinatorial transcriptional complex assembly at specific modules within the interleukin-2 promoter by the immunosuppressant SB203580.
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.
Smith
James L
JL
Advanced Technology Center, Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health, Bethesda, Maryland 20892-4605, USA.
Collins
Irene
I
Chandramouli
G V R
GV
Butscher
Wayne G
WG
Zaitseva
Elena
E
Freebern
Wendy J
WJ
Haggerty
Cynthia M
CM
Doseeva
Victoria
V
Gardner
Kevin
K
D020816:Amino Acid Motifs; D001483:Base Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015233:Models, Statistical; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D007376:Interleukin-2; D011725:Pyridines; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580