Targeting combinatorial transcriptional complex assembly at specific modules within the interleukin-2 promoter by the immunosuppressant SB203580
- PMID: 12896977
- DOI: 10.1074/jbc.M305615200
Targeting combinatorial transcriptional complex assembly at specific modules within the interleukin-2 promoter by the immunosuppressant SB203580
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.
Similar articles
-
The p38 mitogen-activated kinase pathway regulates the human interleukin-10 promoter via the activation of Sp1 transcription factor in lipopolysaccharide-stimulated human macrophages.J Biol Chem. 2001 Apr 27;276(17):13664-74. doi: 10.1074/jbc.M011157200. Epub 2001 Jan 26. J Biol Chem. 2001. PMID: 11278848
-
The p38 MAP kinase inhibitor SB203580 enhances nuclear factor-kappa B transcriptional activity by a non-specific effect upon the ERK pathway.Br J Pharmacol. 2000 Sep;131(1):99-107. doi: 10.1038/sj.bjp.0703534. Br J Pharmacol. 2000. PMID: 10960075 Free PMC article.
-
Induction of human NF-IL6beta by epidermal growth factor is mediated through the p38 signaling pathway and cAMP response element-binding protein activation in A431 cells.Mol Biol Cell. 2005 Jul;16(7):3365-76. doi: 10.1091/mbc.e05-02-0105. Epub 2005 May 18. Mol Biol Cell. 2005. PMID: 15901830 Free PMC article.
-
Opposing roles of serine/threonine kinases MEKK1 and LOK in regulating the CD28 responsive element in T-cells.Biochem J. 2002 Apr 1;363(Pt 1):175-82. doi: 10.1042/0264-6021:3630175. Biochem J. 2002. PMID: 11903060 Free PMC article.
-
Distinct roles for p42/p44 and p38 mitogen-activated protein kinases in the induction of IL-2 by IL-1.Cytokine. 1999 Sep;11(9):643-55. doi: 10.1006/cyto.1998.0478. Cytokine. 1999. PMID: 10479400
Cited by
-
Hydrogen sulfide is an endogenous potentiator of T cell activation.J Biol Chem. 2012 Feb 3;287(6):4211-21. doi: 10.1074/jbc.M111.307819. Epub 2011 Dec 13. J Biol Chem. 2012. PMID: 22167178 Free PMC article.
-
Transcriptional networks inferred from molecular signatures of breast cancer.Am J Pathol. 2008 Feb;172(2):495-509. doi: 10.2353/ajpath.2008.061079. Epub 2008 Jan 10. Am J Pathol. 2008. PMID: 18187569 Free PMC article.
-
Alternative ZAP70-p38 signals prime a classical p38 pathway through LAT and SOS to support regulatory T cell differentiation.Sci Signal. 2019 Jul 23;12(591):eaao0736. doi: 10.1126/scisignal.aao0736. Sci Signal. 2019. PMID: 31337738 Free PMC article.
-
Modulation of IL-2 expression after uptake of hepatitis C virus non-enveloped capsid-like particles: the role of p38 kinase.Cell Mol Life Sci. 2011 Feb;68(3):505-22. doi: 10.1007/s00018-010-0466-8. Epub 2010 Jul 31. Cell Mol Life Sci. 2011. PMID: 20680391 Free PMC article.
-
Multiple mechanisms of growth hormone-regulated gene transcription.Mol Genet Metab. 2007 Feb;90(2):126-33. doi: 10.1016/j.ymgme.2006.10.006. Epub 2006 Nov 28. Mol Genet Metab. 2007. PMID: 17129742 Free PMC article. Review.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous
