Transcriptional control of human T-BET expression: The role of Sp1

Authors

  • Jianhua Yu Dr.,

    Corresponding author
    1. Division of Hematology/Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
    2. Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA
    • The Ohio State University Comprehensive Cancer Center, 458A Starling Loving Hall, 320 West 10thAvenue, Columbus, OH 43210, USA, Fax: +1-614-293-7522
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  • Min Wei,

    1. Division of Hematology/Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
    2. Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA
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  • Zachary Boyd,

    1. Division of Hematology/Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
    2. Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA
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  • Esther B. Lehmann,

    1. Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA
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  • Rossana Trotta,

    1. Division of Hematology/Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
    2. Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA
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  • Hsiaoyin Mao,

    1. Division of Hematology/Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
    2. Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA
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  • Shujun Liu,

    1. Division of Hematology/Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
    2. Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA
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  • Brian Becknell,

    1. Division of Hematology/Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
    2. Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA
    3. Medical Scientist Program, Integrated Biomedical Graduate Program, The Ohio State University, Columbus, OH, USA
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  • Michael S. Jaung,

    1. Division of Hematology/Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
    2. Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA
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  • David Jarjoura,

    1. Center for Biostatistics, College of Public Health, The Ohio State University, Columbus, OH, USA
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  • Guido Marcucci,

    1. Division of Hematology/Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
    2. Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA
    3. The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
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  • Lai-Chu Wu,

    1. Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA
    2. Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA
    3. The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
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  • Michael A. Caligiuri Dr.

    1. Division of Hematology/Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
    2. Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA
    3. The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
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Abstract

Murine T-bet (T-box expressed in T cells) is a master regulator of IFN-γ gene expression in NK and T cells. T-bet also plays a critical role in autoimmunity, asthma and other diseases. However, cis elements or trans factors responsible for regulating T-bet expression remain largely unknown. Here, we report on our discovery of six Sp1-binding sites within the proximal human T-BET promoter that are highly conserved among mammalian species. Electrophoretic mobility shift assays demonstrate a physical association between Sp1 and the proximal T-BET promoter with a direct dose response between Sp1 expression and T-BET promoter activity. Ectopic overexpression of Sp1 also enhanced T-BET expression and cytokine-induced IFN-γ secretion in NK cells and T cells. Mithramycin A, which blocks the binding of Sp1 to the T-BET promoter, diminished both T-BET expression and IFN-γ protein production in monokine-stimulated primary human NK cells. Collectively, our results suggest that Sp1 is a positive transcriptional regulator of T-BET. As T-BET and IFN-γ are critically important in inflammation, infection, and cancer, targeting Sp1, possibly with mithramycin A, may be useful for preventing and/or treating diseases associated with aberrant T-BET or IFN-γ expression.

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