Abstract
The second messenger calcium plays an essential role in the T cell receptor-mediated signal transduction pathways leading to transcription of the interleukin-2 gene. A key mechanism of calcium signaling has been shown to be mediated by calcineurin and NFAT. We report herein that the transcription factor myocyte enhancer factor (MEF)-2 is another calcium signal transducer involved in the regulation of the interleukin (IL)-2 promoter. A MEF2-binding site was identified in proximity to the TATA box of the IL-2 promoter. This site was shown to be bound by MEF2 in both resting and activated T cells. Overexpression of MEF2 enhanced, while overexpression of a dominant negative form of MEF2 or the MEF2-specific transcriptional corepressors Cabin1 and histone deacetylase 4 inhibited, the T cell receptor-dependent activation of an IL-2 reporter gene. Down-regulation of MEF2 by RNA interference in primary human T cells led to the inhibition of endogenous IL-2 transcription. These results suggest that MEF2 is required for the transcriptional activation of IL-2 and likely other cytokine genes in response to calcium signaling and may serve as a novel target for development of immunosuppressants.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Binding Sites
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Calcineurin / metabolism
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Calcium / metabolism*
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Cells, Cultured
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Chromatin / metabolism
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DNA-Binding Proteins / physiology*
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Down-Regulation
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Genes, Dominant
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Genes, Reporter
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Histone Deacetylases / metabolism
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Humans
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Immunosuppressive Agents / pharmacology
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Interleukin-2 / biosynthesis*
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Interleukin-2 / genetics
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Interleukin-2 / metabolism
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Intracellular Signaling Peptides and Proteins
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Jurkat Cells
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MEF2 Transcription Factors
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Mice
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Myogenic Regulatory Factors
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Phosphoproteins / metabolism
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Precipitin Tests
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Promoter Regions, Genetic
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Protein Binding
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RNA Interference
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RNA, Small Interfering / metabolism
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Receptors, Antigen, T-Cell / agonists
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Repressor Proteins / metabolism
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Signal Transduction
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T-Lymphocytes / metabolism*
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Transcription Factors / physiology*
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Transcription, Genetic*
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Transcriptional Activation
Substances
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Adaptor Proteins, Signal Transducing
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CABIN1 protein, human
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Cabin1 protein, mouse
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Chromatin
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DNA-Binding Proteins
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Immunosuppressive Agents
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Interleukin-2
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Intracellular Signaling Peptides and Proteins
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MEF2 Transcription Factors
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Myogenic Regulatory Factors
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Phosphoproteins
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RNA, Small Interfering
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Receptors, Antigen, T-Cell
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Repressor Proteins
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Transcription Factors
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Calcineurin
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HDAC4 protein, human
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Histone Deacetylases
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Calcium