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*
Department of Immunology and
Division of Infectious Diseases, Mayo Clinic, Rochester, MN 55905;
Department of Immunobiology, Immunex Corp., Seattle, WA 98101
Activation-induced cell death of peripheral T cells results from the interaction between Fas and Fas ligand. Resting peripheral T cells are resistant to Fas-induced apoptosis and become susceptible only after their activation. We have investigated the molecular mechanism mediating the sensitization of resting peripheral T cells to Fas-mediated apoptosis following TCR stimulation. TCR activation decreases the steady state protein levels of FLIP (FLICE-like inhibitory protein), an inhibitor of the Fas signaling pathway. Reconstitution of intracellular FLIP levels by the addition of a soluble HIV transactivator protein-FLIP chimera completely restores resistance to Fas-mediated apoptosis in TCR primary T cells. Inhibition of IL-2 production by cyclosporin A, or inhibition of IL-2 signaling by rapamycin or anti-IL-2 neutralizing Abs prevents the decrease in FLIP levels and confers resistance to Fas-mediated apoptosis following T cell activation. Using cell cycle-blocking agents, we demonstrate that activated T cells arrested in G1 phase contain high levels of FLIP protein, whereas activated T cells arrested in S phase have decreased FLIP protein levels. These findings link regulation of FLIP protein levels with cell cycle progression and provide an explanation for the increase in TCR-induced apoptosis observed during the S phase of the cell cycle.
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S. A. Trushin, K. N. Pennington, A. Algeciras-Schimnich, and C. V. Paya Protein Kinase C and Calcineurin Synergize to Activate Ikappa B Kinase and NF-kappa B in T Lymphocytes J. Biol. Chem., August 13, 1999; 274(33): 22923 - 22931. [Abstract] [Full Text] [PDF]
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D. J. Panka, T. Mano, T. Suhara, K. Walsh, and J. W. Mier Phosphatidylinositol 3-Kinase/Akt Activity Regulates c-FLIP Expression in Tumor Cells J. Biol. Chem., March 2, 2001; 276(10): 6893 - 6896. [Abstract] [Full Text] [PDF]
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A. Krueger, I. Schmitz, S. Baumann, P. H. Krammer, and S. Kirchhoff Cellular FLICE-inhibitory Protein Splice Variants Inhibit Different Steps of Caspase-8 Activation at the CD95 Death-inducing Signaling Complex J. Biol. Chem., June 1, 2001; 276(23): 20633 - 20640. [Abstract] [Full Text] [PDF]
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