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Wu, Wenfang

Cell and Molecular Biology Program

2006

Ph. D.

The NFAT family of transcription factors are important in regulating expression of a broad array of genes, including cytokines, T cell surface receptors, and certain transcription factors. NFATc1 and NFATc2 are two principal NFAT members that are expressed in peripheral T cells. Levels of NFAT expression in T cells are partly transcriptionally regulated, but less is understood regarding its post-transcriptional control. In this thesis I show that NFATc1 and NFATc2 are rapidly degraded in apoptotic T cells. NFATc2 is highly sensitive to cleavage by caspase-3, whereas NFATc1 is only weakly sensitive to caspase-3 or caspase-8. Two potential caspase-3 cleavage sites were identified in the N-terminal transactivation domain of NFATc2. They were confirmed by in vitro caspase cleavage assays. Abolition of NFATc2 cleavage by mutating these two cleavage sites resulted in augmented NFAT transcriptional activity. Of particular interest was that non-apoptotic T cells from c-FLIPL-Tg mice that manifest elevated caspase activity, have greatly reduced levels of NFATc2 protein and NFAT transcriptional activity. Furthermore, NFAT transcriptional activity could be augmented in wild-type effector T cells by inhibition of caspase activity. My work revealed a new post-transcriptional regulation specific for NFATc2, which operates not only during apoptosis, but also in non-apoptotic T cells.