Myocyte enhancer factor 2 mediates calcium-dependent transcription of the interleukin-2 gene in T lymphocytes: a calcium signaling module that is distinct from but collaborates with the nuclear factor of activated T cells (NFAT).
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.
Pan
Fan
F
Department of Pharmacology and Molecular Science and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Ye
Zhaohui
Z
Cheng
Linzhao
L
Liu
Jun O
JO
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001665:Binding Sites; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation; D005799:Genes, Dominant; D017930:Genes, Reporter; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D064326:MEF2 Transcription Factors; D051379:Mice; D018006:Myogenic Regulatory Factors; D010750:Phosphoproteins / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000819:agonists; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D048868:Adaptor Proteins, Signal Transducing; C491861:CABIN1 protein, human; C113151:Cabin1 protein, mouse; D002843:Chromatin; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D012097:Repressor Proteins; D014157:Transcription Factors; D019703:Calcineurin; C400300:HDAC4 protein, human; D006655:Histone Deacetylases; D002118:Calcium