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    SIRT1 deacetylation regulates NFAT transcriptional activity

    Shannon, Stephen G., 1975-
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    Date
    2009
    Format
    Thesis
    Metadata
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    Abstract
    [ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] The class III histone deacetylase SIRT1 plays important roles in aging, metabolism and biological clock control. We have recently demonstrated that SIRT1 is a critical factor to control immune functions. However, the underlying molecular mechanisms by which SIRT1 regulates T cell immune responses remain unclear. We hypothesize that SIRT1 inhibits the transcriptional activation of the nuclear factor of activated T cells (NFAT), a critical factor in the regulation of T-cell activation and anergy. To support this hypothesis, we have demonstrated that overexpression of SIRT1, or the treatment of cells with the SIRT1 activator, resveratrol, dramatically inhibits NFAT transcriptional activity. In addition, EMSA experiments revealed that SIRT1 suppresses NFAT transcriptional activity in mouse primary T cells, because loss of SIRT1 functions resulted in a significant increase of the promoter binding activity of NFAT. SIRT1 inhibits NFAT transcriptional activity by directly interacting with NFAT in transiently transfected HEK293 cells and in mouse primary T cells. The C-terminus of SIRT1 is responsible for its interaction with NFAT, because the deletion of the SIRT1 C-terminus impairs its ability to interact with NFAT and exert its suppressive activity on NFAT transcription. Additionally, we have shown that SIRT1 can deacetylate NFAT in 293HEK cells. Importantly, the interaction of SIRT1 with NFAT is regulated by TCR-initiated calcium signaling. Moreover, over expression of SIRT1, or treatment with the SIRT1 activator resveratrol, inhibited NFAT acetylation. Mutation of the histone deacetylase catalytic domain of SIRT1 completely abolished its ability to inhibit NFAT acetylation. Our findings here identified a novel molecular mechanism of the epigenetic regulation of T cell immune response by SIRT1.
    URI
    https://doi.org/10.32469/10355/10136
    https://hdl.handle.net/10355/10136
    Degree
    M.A.
    Thesis Department
    Biological sciences (MU)
    Rights
    Access is limited to the campus of the University of Missouri--Columbia.
    Collections
    • 2009 MU theses - Access restricted to MU
    • Biological Sciences electronic theses and disserations (MU)

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