MITOGEN-ACTIVATED PROTEIN-KINASE KINASE ANTAGONIZED FAS-ASSOCIATED DEATH DOMAIN PROTEIN-MEDIATED APOPTOSIS BY INDUCED FLICE-INHIBITORY PROTEIN EXPRESSION

Fas and Fas-associated death domain (FADD) play a critical role in the homeostasis of different cell types. The regulation of Fas and FADD-m ediated cell death is pivotal to many physiological functions. The act ivation of T lymphocytes by concanavalin A (Con A) inhibited Fas-media ted cell death. We identified that among the several activation signal s downstream of Con A stimulation, mitogen-activated protein (MAP) kin ase kinase (MKK) was the major kinase pathway that antagonized Fas-tri ggered cell death. MKK1 suppressed FADD- but not caspase-3-induced apo ptosis, indicating that antagonism occurred early along the Fas-initia ted apoptotic cascade. We further demonstrated that activation of MKK1 led to expression of FLIP, a specific inhibitor of FADD. MKK1 inhibit ion of FADD-induced cell death was abrogated if induction of FLIP was prevented, indicating that FLIP mediates MKK1 suppression of FADD-medi ated apoptosis. Our results illustrate a general mechanism by which ac tivation of MAP kinase attenuates apoptotic signals initiated by death receptors in normal and transformed cells.