Mitogen-activated Protein Kinase Kinase Antagonized Fas-associated Death Domain Protein–mediated Apoptosis by Induced FLICE-inhibitory Protein Expression |
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Authors: | Jung-Hua Yeh Shu-Ching Hsu Shou-Hwa Han Ming-Zong Lai |
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Affiliation: | From the *Graduate Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 11217, Taiwan; the ‡Institute of Molecular Biology, Academia Sinica, Nankang, Taipei 11529, Taiwan; and the §Graduate Institute of Microbiology, National Taiwan University School of Medicine, Taipei 10018, Taiwan |
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Abstract: | Fas and Fas-associated death domain (FADD) play a critical role in the homeostasis of different cell types. The regulation of Fas and FADD-mediated cell death is pivotal to many physiological functions. The activation of T lymphocytes by concanavalin A (Con A) inhibited Fas-mediated cell death. We identified that among the several activation signals downstream of Con A stimulation, mitogen-activated protein (MAP) kinase kinase (MKK) was the major kinase pathway that antagonized Fas-triggered cell death. MKK1 suppressed FADD- but not caspase-3– induced apoptosis, indicating that antagonism occurred early along the Fas-initiated apoptotic cascade. We further demonstrated that activation of MKK1 led to expression of FLIP, a specific inhibitor of FADD. MKK1 inhibition of FADD-induced cell death was abrogated if induction of FLIP was prevented, indicating that FLIP mediates MKK1 suppression of FADD-mediated apoptosis. Our results illustrate a general mechanism by which activation of MAP kinase attenuates apoptotic signals initiated by death receptors in normal and transformed cells. |
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Keywords: | mitogen-activated protein kinase kinase Fas-associated death domain protein Fas FLIP apoptosis |
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