MUC1 oncoprotein blocks death receptor-mediated apoptosis by inhibiting recruitment of caspase-8

Stimulation of the death receptor superfamily induces the activation of caspase-8 and thereby the apoptotic response. The MUCI oncoprotein is aberrantly overexpressed by diverse human malignancies and inhibits stress-induced apoptosis. The present results show that MUCI blocks activation of caspase-8 and apoptosis in the response of malignant cells to tumor necrosis factor cy, tumor necrosis factor-related apoptosis-inducing ligand, and Fas ligand. The results show that MUCI associates constitutively with caspase-8. The MUCI cytoplasmic domain (MUCI-CD) binds directly to the caspase-8 p18 fragment upstream to the catalytic Cys 360 site. The results also show that MUCI-CD binds to Fasassociated death domain (FADD) at the death effector domain. In nonmalignant epithelial cells, MUCI interacts with caspase8 and FADD as an induced response to death receptor stimulation. The functional significance of these interactions is supported by the demonstration that MUCI competes with caspase-8 for binding to FADD and blocks recruitment of caspase-8 to the death-inducing signaling complex. These findings indicate that MUCI is of importance to the physiologic regulation of caspase-8 activity and that overexpression of MUCI, as found in human malignancies, could contribute to constitutive inhibition of death receptor signaling pathways.