Myocyte Enhancer Factor 2 Mediates Calcium-dependent Transcription of the Interleukin-2 Gene in T Lymphocytes (2004)

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. 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. Activation of peripheral T cells through the engagement of TCR 1The abbreviations used are: TCR, T cell receptor; IL, interleukin; NFAT, nuclear factor of activated T cells; MEF, myocyte enhancer factor; siRNA, small interfering RNA; EMSA, electrophoretic gel mobility shift assay; PMA, phorbol 12-myristate 13-acetate; CHIP, chromatin immunoprecipitation-PCR; GFP, green fluorescent protein; TU, transducing units; FACS, fluorescence-activated cell sorter; RT, reverse transcriptase; ELISA, enzyme-linked immunosorbent assay; GAPDH, glyceraldehyde-6-phosphate dehydrogenase; CNBD, calcineurin-binding domain. 1The abbreviations used are: TCR, T cell receptor; IL, interleukin; NFAT, nuclear factor of activated T cells; MEF, myocyte enhancer factor; siRNA, small interfering RNA; EMSA, electrophoretic gel mobility shift assay; PMA, phorbol 12-myristate 13-acetate; CHIP, chromatin immunoprecipitation-PCR; GFP, green fluorescent protein; TU, transducing units; FACS, fluorescence-activated cell sorter; RT, reverse transcriptase; ELISA, enzyme-linked immunosorbent assay; GAPDH, glyceraldehyde-6-phosphate dehydrogenase; CNBD, calcineurin-binding domain. with major histocompatibility complex-peptide complexes on antigen presenting cells leads to the transcriptional activation of a number of cytokine genes that are involved in the orchestration of the cellular immune response. Prominent among the cytokines secreted by activated T cells is IL-2, which plays an essential role in subsequent T cell proliferation and homeostasis (1Smith K.A. Curr. Opin. Immunol. 1992; 4: 271-276Crossref PubMed Scopus (102) Google Scholar). The intracellular signal transduction pathway linking TCR and the IL-2 promoter has been used as a paradigm to elucidate mechanisms of signaling from cell surface to the nucleus. The second messenger calcium has been shown to be an essential mediator of the TCR signaling pathway. Through the use of the immunosuppressive natural products CsA and FK506, both of which inhibit a calcium-dependent signaling step leading to IL-2 transcription, a key downstream transducer of calcium signaling was identified as the calcium, and calmodulin-dependent protein phosphatase calcineurin (2Liu J. Farmer J.D. Lane W.S. Friedman J. Weissman I. Schreiber S.L. Cell. 1991; 66: 807-815Abstract Full Text PubMed Scopus Google J. Weissman I. Cell. 1991; 66: Full Text PubMed Scopus Google J. 1992; PubMed Scopus Google 1992; PubMed Scopus Google J. 1992; PubMed Scopus Google 1992; PubMed Scopus Google J. Immunol. 1992; PubMed Scopus Google as protein phosphatase The primary calcineurin to be of the nuclear factor of activated T cells protein 1991; PubMed Scopus Google J. PubMed Scopus Google Immunol. PubMed Scopus Google calcium signaling mediated by the transcription factor MEF2 Full Text Full Text PubMed Scopus Google was identified and shown to be involved in the regulation of the J.D. Cell. PubMed Scopus Google PubMed Scopus Google Full Text Full Text PubMed Scopus Google J. PubMed Scopus Google Scholar). NFAT, MEF2 is bound to in the of the intracellular calcium MEF2 a of transcriptional Cabin1 as Full Text Full Text PubMed Scopus Google J. Full Text Full Text PubMed Scopus Google MEF2 transcriptional and and PubMed Scopus Google J. J. PubMed Scopus Google J. PubMed Scopus Google Scholar). These MEF2-specific corepressors histone to promoter which the chromatin the promoter calcium MEF2 are from MEF2 by activated to to as on transcription of the target genes PubMed Scopus Google J. Full Text Full Text PubMed Scopus Google Scholar). The of MEF2 transcriptional has been shown to be to regulation by calmodulin-dependent another mechanism of activation of MEF2 by calcium J. PubMed Scopus Google J. PubMed Scopus Google an to the role of Cabin1 in in a Cabin1 in which the and MEF2-binding are J. J. PubMed Scopus Google Scholar). The are in development the of the MEF2-binding of likely the of Cabin1 and other MEF2 corepressors in the of a number of cytokines IL-2, and with TCR of the that of cytokines was to the that other as MEF2 a role in the of IL-2 and other cytokine and T cells and as Full Text Full Text PubMed Scopus Google Scholar). The of reporter was a used was from the IL-2 promoter to and the MEF2-binding site as with Full Text Full Text PubMed Scopus Google Scholar). The was and the reverse was of for is to that with PubMed Scopus Google Scholar). of to of human by and the and MEF2-binding in to the TATA of the IL-2 the IL-2 promoter for a MEF2-binding and a of A or T was and in the IL-2 promoter from the MEF2-binding J.D. PubMed Scopus Google the are The MEF2-binding site in the human IL-2 promoter from that in the IL-2 promoter in a from an in the human to a in the the required for MEF2 the MEF2-binding site in the IL-2 promoter is of to a the site and nuclear of T a which was to by an of in the the was that MEF2 was bound by the These results that the MEF2-binding site in the IL-2 promoter MEF2 in to the IL-2 in the to MEF2 is bound to the IL-2 promoter in and the is mediated by the MEF2-binding We the of MEF2 to the endogenous IL-2 promoter the PubMed Scopus Google Scholar). the of MEF2 in T is bound to the promoter of IL-2 to with the promoter in T cell the of to the endogenous IL-2 promoter is of the activation of T cells and a negative to the promoter of the a of PubMed Scopus Google Scholar). to the promoter that the of MEF2 to the IL-2 promoter was is bound to the IL-2 promoter the MEF2-binding site in and is of Cabin1 and to the IL-2 promoter. to the of MEF2 and Cabin1 4 and and and to the endogenous IL-2 promoter. of from T cells with and or IL-2 reporter or a in which the MEF2-binding site has been has been shown that the MEF2-specific transcriptional corepressors Cabin1 and are bound to MEF2 in a calcium-dependent PubMed Scopus Google J. Full Text Full Text PubMed Scopus Google Scholar). These are from MEF2 calcium We Cabin1 and with the IL-2 promoter Cabin1 and to be with the IL-2 promoter in T cells 4 and with and with the of calcium in the Cabin1 and from MEF2 and the IL-2 promoter and These results suggest that MEF2 is likely to a negative role in the transcription of the IL-2 promoter through of of corepressors Cabin1 and in resting T the MEF2-binding site in the IL-2 promoter is for the of the IL-2 promoter or a in which the MEF2-binding site has been shown in MEF2 was bound to the IL-2 promoter in the or the of with and and with the of endogenous of the MEF2-binding in the IL-2 promoter the of MEF2 to the IL-2 promoter 4 and that used for the of the IL-2 promoter that the endogenous is results that MEF2 is bound to the IL-2 promoter through the MEF2-binding of MEF2 the Activation of the IL-2 in a MEF2 of MEF2 to the IL-2 promoter that overexpression of MEF2 the of MEF2 to endogenous MEF2 the transcriptional of MEF2 as J. PubMed Scopus Google Scholar). overexpression of MEF2 the IL-2 reporter activation in response to by and MEF2 is to be to of corepressors Cabin1 or the of Cabin1 and on the activation of the IL-2 reporter by and Overexpression of or Cabin1 the activation of the IL-2 reporter in response to and overexpression of which to MEF2 is of the a on IL-2 promoter to the MEF2-binding Cabin1 a calcineurin-binding which may for the inhibition of IL-2 reporter by calcineurin We a of Cabin1 the calcineurin-binding PubMed Scopus Google Scholar). was in T of IL-2 reporter with the These results the that MEF2 is involved in the activation of the IL-2 and dominant negative MEF2 or MEF2-specific IL-2 reporter T cells with IL-2 reporter with as with for for of and of the MEF2-binding site in the IL-2 or MEF2 Activation of the IL-2 the role of MEF2 in IL-2 transcription in response to calcium the MEF2-binding site in the IL-2 reporter gene. This was shown to be in MEF2 in by the The activation of the reporter from a in response to by and the the MEF2 reporter be activated by overexpression of be by which MEF2 to with the IL-2 promoter. the MEF2-binding site in the IL-2 promoter plays a role in a of the of MEF2 in IL-2 a dominant negative form of the J.D. Cell. PubMed Scopus Google J. Full Text Full Text PubMed Scopus (102) Google and on the IL-2 reporter activation by and Overexpression of the the activation of the IL-2 reporter that MEF2 is required for IL-2 promoter of MEF2 by RNA of IL-2 in to by TCR the role of MEF2 in IL-2 transcriptional activation in RNA interference to the of MEF2 in primary human T cells and the on endogenous IL-2 and protein are of to The of MEF2 in T cells is of for an siRNA, identified an which in T cells by the to primary human T used of transducing both activated and T cells PubMed Scopus Google PubMed Scopus Google Scholar). We a RNA and the the on the PubMed Scopus Google and the T cells from human peripheral with and by The transduction by both was to be on in by the MEF2 the of The of the to be for as on the protein of endogenous the human primary T cells T with a of and IL-2 transcription was in cells with the A in IL-2 was in the T cell with the with the in RNA the of IL-2 protein secreted the was in human T cells with the of a with T cell is that the of IL-2 transcription is to an of on T cell The of and IL-2 in human T cells was likely by as of the human T cells and of MEF2 and These suggest that MEF2 is for the transcriptional activation of IL-2 peripheral T cell interference of MEF2 leads to inhibition of IL-2 promoter inhibition of MEF2 by from primary human T cells with or to or RNA interference with MEF2 IL-2 in response to by and The of primary human T cells with a of and RNA was from and to RNA interference with MEF2 IL-2 in response to by IL-2 protein secreted the was by a calcium transcription MEF2 has been shown to a key role in calcium from the to of genes involved in and cell We shown that the calcium signaling is involved in transcription of IL-2 T cell calcium signaling MEF2 and the other of calcineurin and NFAT, are involved in calcium to the IL-2 promoter and of the MEF2-binding site in the IL-2 promoter that MEF2-binding are likely to be in the of other genes to be by of in primary human T cells a in the of IL-2 and of IL-2 in primary human T cells in response to by TCR that MEF2 is for activation of the IL-2 promoter. These results suggest that MEF2 may serve as a target for novel that IL-2 and T cell Activation of peripheral T cells through the engagement of TCR 1The abbreviations used are: TCR, T cell receptor; IL, interleukin; NFAT, nuclear factor of activated T cells; MEF, myocyte enhancer factor; siRNA, small interfering RNA; EMSA, electrophoretic gel mobility shift assay; PMA, phorbol 12-myristate 13-acetate; CHIP, chromatin immunoprecipitation-PCR; GFP, green fluorescent protein; TU, transducing units; FACS, fluorescence-activated cell sorter; RT, reverse transcriptase; ELISA, enzyme-linked immunosorbent assay; GAPDH, glyceraldehyde-6-phosphate dehydrogenase; CNBD, calcineurin-binding domain. 1The abbreviations used are: TCR, T cell receptor; IL, interleukin; NFAT, nuclear factor of activated T cells; MEF, myocyte enhancer factor; siRNA, small interfering RNA; EMSA, electrophoretic gel mobility shift assay; PMA, phorbol 12-myristate 13-acetate; CHIP, chromatin immunoprecipitation-PCR; GFP, green fluorescent protein; TU, transducing units; FACS, fluorescence-activated cell sorter; RT, reverse transcriptase; ELISA, enzyme-linked immunosorbent assay; GAPDH, glyceraldehyde-6-phosphate dehydrogenase; CNBD, calcineurin-binding domain. with major histocompatibility complex-peptide complexes on antigen presenting cells leads to the transcriptional activation of a number of cytokine genes that are involved in the orchestration of the cellular immune response. Prominent among the cytokines secreted by activated T cells is IL-2, which plays an essential role in subsequent T cell proliferation and homeostasis (1Smith K.A. Curr. Opin. Immunol. 1992; 4: 271-276Crossref PubMed Scopus (102) Google Scholar). The intracellular signal transduction pathway linking TCR and the IL-2 promoter has been used as a paradigm to elucidate mechanisms of signaling from cell surface to the nucleus. The second messenger calcium has been shown to be an essential mediator of the TCR signaling pathway. Through the use of the immunosuppressive natural products CsA and FK506, both of which inhibit a calcium-dependent signaling step leading to IL-2 transcription, a key downstream transducer of calcium signaling was identified as the calcium, and calmodulin-dependent protein phosphatase calcineurin (2Liu J. Farmer J.D. Lane W.S. Friedman J. Weissman I. Schreiber S.L. Cell. 1991; 66: 807-815Abstract Full Text PubMed Scopus Google J. Weissman I. Cell. 1991; 66: Full Text PubMed Scopus Google J. 1992; PubMed Scopus Google 1992; PubMed Scopus Google J. 1992; PubMed Scopus Google 1992; PubMed Scopus Google J. Immunol. 1992; PubMed Scopus Google as protein phosphatase The primary calcineurin to be of the nuclear factor of activated T cells protein 1991; PubMed Scopus Google J. PubMed Scopus Google Immunol. PubMed Scopus Google Scholar). calcium signaling mediated by the transcription factor MEF2 Full Text Full Text PubMed Scopus Google was identified and shown to be involved in the regulation of the J.D. Cell. PubMed Scopus Google PubMed Scopus Google Full Text Full Text PubMed Scopus Google J. PubMed Scopus Google Scholar). NFAT, MEF2 is bound to in the of the intracellular calcium MEF2 a of transcriptional Cabin1 as Full Text Full Text PubMed Scopus Google J. Full Text Full Text PubMed Scopus Google MEF2 transcriptional and and PubMed Scopus Google J. J. PubMed Scopus Google J. PubMed Scopus Google Scholar). These MEF2-specific corepressors histone to promoter which the chromatin the promoter calcium MEF2 are from MEF2 by activated to to as on transcription of the target genes PubMed Scopus Google J. Full Text Full Text PubMed Scopus Google Scholar). The of MEF2 transcriptional has been shown to be to regulation by calmodulin-dependent another mechanism of activation of MEF2 by calcium J. PubMed Scopus Google J. PubMed Scopus Google Scholar). an to the role of Cabin1 in in a Cabin1 in which the and MEF2-binding are J. J. PubMed Scopus Google Scholar). The are in development the of the MEF2-binding of likely the of Cabin1 and other MEF2 corepressors in the of a number of cytokines IL-2, and with TCR of the that of cytokines was to the that other as MEF2 a role in the of IL-2 and other cytokine and T cells and as Full Text Full Text PubMed Scopus Google Scholar). The of reporter was a used was from the IL-2 promoter to and the MEF2-binding site as with Full Text Full Text PubMed Scopus Google Scholar). The was and the reverse was of for is to that with PubMed Scopus Google Scholar). of to of human by and the and and T cells and as Full Text Full Text PubMed Scopus Google Scholar). The of reporter was a used was from the IL-2 promoter to and the MEF2-binding site as with Full Text Full Text PubMed Scopus Google Scholar). The was and the reverse was of for is to that with PubMed Scopus Google Scholar). of to of human by and the and MEF2-binding in to the TATA of the IL-2 the IL-2 promoter for a MEF2-binding and a of A or T was and in the IL-2 promoter from the MEF2-binding J.D. PubMed Scopus Google the are The MEF2-binding site in the human IL-2 promoter from that in the IL-2 promoter in a from an in the human to a in the the required for MEF2 the MEF2-binding site in the IL-2 promoter is of to a the site and nuclear of T a which was to by an of in the the was that MEF2 was bound by the These results that the MEF2-binding site in the IL-2 promoter MEF2 in to the IL-2 in the to MEF2 is bound to the IL-2 promoter in and the is mediated by the MEF2-binding We the of MEF2 to the endogenous IL-2 promoter the PubMed Scopus Google Scholar). the of MEF2 in T is bound to the promoter of IL-2 to with the promoter in T cell the of to the endogenous IL-2 promoter is of the activation of T cells and a negative to the promoter of the a of PubMed Scopus Google Scholar). to the promoter that the of MEF2 to the IL-2 promoter was has been shown that the MEF2-specific transcriptional corepressors Cabin1 and are bound to MEF2 in a calcium-dependent PubMed Scopus Google J. Full Text Full Text PubMed Scopus Google Scholar). These are from MEF2 calcium We Cabin1 and with the IL-2 promoter Cabin1 and to be with the IL-2 promoter in T cells 4 and with and with the of calcium in the Cabin1 and from MEF2 and the IL-2 promoter and These results suggest that MEF2 is likely to a negative role in the transcription of the IL-2 promoter through of of corepressors Cabin1 and in resting T the MEF2-binding site in the IL-2 promoter is for the of the IL-2 promoter or a in which the MEF2-binding site has been shown in MEF2 was bound to the IL-2 promoter in the or the of with and and with the of endogenous of the MEF2-binding in the IL-2 promoter the of MEF2 to the IL-2 promoter 4 and that used for the of the IL-2 promoter that the endogenous is results that MEF2 is bound to the IL-2 promoter through the MEF2-binding of MEF2 the Activation of the IL-2 in a MEF2 of MEF2 to the IL-2 promoter that overexpression of MEF2 the of MEF2 to endogenous MEF2 the transcriptional of MEF2 as J. PubMed Scopus Google Scholar). overexpression of MEF2 the IL-2 reporter activation in response to by and MEF2 is to be to of corepressors Cabin1 or the of Cabin1 and on the activation of the IL-2 reporter by and Overexpression of or Cabin1 the activation of the IL-2 reporter in response to and overexpression of which to MEF2 is of the a on IL-2 promoter to the MEF2-binding Cabin1 a calcineurin-binding which may for the inhibition of IL-2 reporter by calcineurin We a of Cabin1 the calcineurin-binding PubMed Scopus Google Scholar). was in T of IL-2 reporter with the These results the that MEF2 is involved in the activation of the IL-2 and dominant negative MEF2 or MEF2-specific IL-2 reporter T cells with IL-2 reporter with as with for for of and of the MEF2-binding site in the IL-2 or MEF2 Activation of the IL-2 the role of MEF2 in IL-2 transcription in response to calcium the MEF2-binding site in the IL-2 reporter gene. This was shown to be in MEF2 in by the The activation of the reporter from a in response to by and the the MEF2 reporter be activated by overexpression of be by which MEF2 to with the IL-2 promoter. the MEF2-binding site in the IL-2 promoter plays a role in a of the of MEF2 in IL-2 a dominant negative form of the J.D. Cell. PubMed Scopus Google J. Full Text Full Text PubMed Scopus (102) Google and on the IL-2 reporter activation by and Overexpression of the the activation of the IL-2 reporter that MEF2 is required for IL-2 promoter of MEF2 by RNA of IL-2 in to by TCR the role of MEF2 in IL-2 transcriptional activation in RNA interference to the of MEF2 in primary human T cells and the on endogenous IL-2 and protein are of to The of MEF2 in T cells is of for an siRNA, identified an which in T cells by the to primary human T used of transducing both activated and T cells PubMed Scopus Google PubMed Scopus Google Scholar). We a RNA and the the on the PubMed Scopus Google and the T cells from human peripheral with and by The transduction by both was to be on in by the MEF2 the of The of the to be for as on the protein of endogenous the human primary T cells T with a of and IL-2 transcription was in cells with the A in IL-2 was in the T cell with the with the in RNA the of IL-2 protein secreted the was in human T cells with the of a with T cell is that the of IL-2 transcription is to an of on T cell The of and IL-2 in human T cells was likely by as of the human T cells and of MEF2 and These suggest that MEF2 is for the transcriptional activation of IL-2 peripheral T cell interference of MEF2 leads to inhibition of IL-2 promoter inhibition of MEF2 by from primary human T cells with or to or RNA interference with MEF2 IL-2 in response to by and The of primary human T cells with a of and RNA was from and to RNA interference with MEF2 IL-2 in response to by IL-2 protein secreted the was by a calcium transcription MEF2 has been shown to a key role in calcium from the to of genes involved in and cell We shown that the calcium signaling is involved in transcription of IL-2 T cell calcium signaling MEF2 and the other of calcineurin and NFAT, are involved in calcium to the IL-2 promoter and of the MEF2-binding site in the IL-2 promoter that MEF2-binding are likely to be in the of other genes to be by of in primary human T cells a in the of IL-2 and of IL-2 in primary human T cells in response to by TCR that MEF2 is for activation of the IL-2 promoter. These results suggest that MEF2 may serve as a target for novel that IL-2 and T cell A MEF2-binding in to the TATA of the IL-2 the IL-2 promoter for a MEF2-binding and a of A or T was and in the IL-2 promoter from the MEF2-binding J.D. PubMed Scopus Google the are The MEF2-binding site in the human IL-2 promoter from that in the IL-2 promoter in a from an in the human to a in the the required for MEF2 the MEF2-binding site in the IL-2 promoter is of to a the site and nuclear of T a which was to by an of in the the was that MEF2 was bound by the These results that the MEF2-binding site in the IL-2 promoter MEF2 in MEF2 to the IL-2 in the to MEF2 is bound to the IL-2 promoter in and the is mediated by the MEF2-binding We the of MEF2 to the endogenous IL-2 promoter the PubMed Scopus Google Scholar). the of MEF2 in T is bound to the promoter of IL-2 to with the promoter in T cell the of to the endogenous IL-2 promoter is of the activation of T cells and a negative to the promoter of the a of PubMed Scopus Google Scholar). to the promoter that the of MEF2 to the IL-2 promoter was has been shown that the MEF2-specific transcriptional corepressors Cabin1 and are bound to MEF2 in a calcium-dependent PubMed Scopus Google J. Full Text Full Text PubMed Scopus Google Scholar). These are from MEF2 calcium We Cabin1 and with the IL-2 promoter Cabin1 and to be with the IL-2 promoter in T cells 4 and with and with the of calcium in the Cabin1 and from MEF2 and the IL-2 promoter and These results suggest that MEF2 is likely to a negative role in the transcription of the IL-2 promoter through of of corepressors Cabin1 and in resting T cells. the MEF2-binding site in the IL-2 promoter is for the of the IL-2 promoter or a in which the MEF2-binding site has been shown in MEF2 was bound to the IL-2 promoter in the or the of with and and with the of endogenous of the MEF2-binding in the IL-2 promoter the of MEF2 to the IL-2 promoter 4 and that used for the of the IL-2 promoter that the endogenous is results that MEF2 is bound to the IL-2 promoter through the MEF2-binding Overexpression of MEF2 the Activation of the IL-2 in a MEF2 of MEF2 to the IL-2 promoter that overexpression of MEF2 the of MEF2 to endogenous MEF2 the transcriptional of MEF2 as J. PubMed Scopus Google Scholar). overexpression of MEF2 the IL-2 reporter activation in response to by and MEF2 is to be to of corepressors Cabin1 or the of Cabin1 and on the activation of the IL-2 reporter by and Overexpression of or Cabin1 the activation of the IL-2 reporter in response to and overexpression of which to MEF2 is of the a on IL-2 promoter to the MEF2-binding Cabin1 a calcineurin-binding which may for the inhibition of IL-2 reporter by calcineurin We a of Cabin1 the calcineurin-binding PubMed Scopus Google Scholar). was in T of IL-2 reporter with the These results the that MEF2 is involved in the activation of the IL-2 promoter. of the MEF2-binding site in the IL-2 or MEF2 Activation of the IL-2 the role of MEF2 in IL-2 transcription in response to calcium the MEF2-binding site in the IL-2 reporter gene. This was shown to be in MEF2 in by the The activation of the reporter from a in response to by and the the MEF2 reporter be activated by overexpression of be by which MEF2 to with the IL-2 promoter. the MEF2-binding site in the IL-2 promoter plays a role in a of the of MEF2 in IL-2 a dominant negative form of the J.D. Cell. PubMed Scopus Google J. Full Text Full Text PubMed Scopus (102) Google and on the IL-2 reporter activation by and Overexpression of the the activation of the IL-2 reporter that MEF2 is required for IL-2 promoter Down-regulation of MEF2 by RNA of IL-2 in to by TCR the role of MEF2 in IL-2 transcriptional activation in RNA interference to the of MEF2 in primary human T cells and the on endogenous IL-2 and protein are of to The of MEF2 in T cells is of for an siRNA, identified an which in T cells by the to primary human T used of transducing both activated and T cells PubMed Scopus Google PubMed Scopus Google Scholar). We a RNA and the the on the PubMed Scopus Google and the T cells from human peripheral with and by The transduction by both was to be on in by the MEF2 the of The of the to be for as on the protein of endogenous the human primary T cells T with a of and IL-2 transcription was in cells with the A in IL-2 was in the T cell with the with the in RNA the of IL-2 protein secreted the was in human T cells with the of a with T cell is that the of IL-2 transcription is to an of on T cell The of and IL-2 in human T cells was likely by as of the human T cells and of MEF2 and These suggest that MEF2 is for the transcriptional activation of IL-2 peripheral T cell a calcium transcription MEF2 has been shown to a key role in calcium from the to of genes involved in and cell We shown that the calcium signaling is involved in transcription of IL-2 T cell calcium signaling MEF2 and the other of calcineurin and NFAT, are involved in calcium to the IL-2 promoter and of the MEF2-binding site in the IL-2 promoter that MEF2-binding are likely to be in the of other genes to be by of in primary human T cells a in the of IL-2 and of IL-2 in primary human T cells in response to by TCR that MEF2 is for activation of the IL-2 promoter. These results suggest that MEF2 may serve as a target for novel that IL-2 and T cell with with