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 MUC1 oncoprotein is aberrantly overexpressed by diverse human malignancies and inhibits stress-induced apoptosis. The present results show that MUC1 blocks activation of caspase-8 and apoptosis in the response of malignant cells to tumor necrosis factor alpha, tumor necrosis factor-related apoptosis-inducing ligand, and Fas ligand. The results show that MUC1 associates constitutively with caspase-8. The MUC1 cytoplasmic domain (MUC1-CD) binds directly to the caspase-8 p18 fragment upstream to the catalytic Cys(360) site. The results also show that MUC1-CD binds to Fas-associated death domain (FADD) at the death effector domain. In nonmalignant epithelial cells, MUC1 interacts with caspase-8 and FADD as an induced response to death receptor stimulation. The functional significance of these interactions is supported by the demonstration that MUC1 competes with caspase-8 for binding to FADD and blocks recruitment of caspase-8 to the death-inducing signaling complex. These findings indicate that MUC1 is of importance to the physiologic regulation of caspase-8 activity and that overexpression of MUC1, as found in human malignancies, could contribute to constitutive inhibition of death receptor signaling pathways.
Agata
Naoki
N
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Ahmad
Rehan
R
Kawano
Takeshi
T
Raina
Deepak
D
Kharbanda
Surender
S
Kufe
Donald
D
D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D053181:Caspase 8 / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D018396:Mucin-1 / Q000502:physiology*; D034741:RNA, Small Interfering; D053218:Receptors, Death Domain / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction
C060192:MUC1 protein, human; D018396:Mucin-1; D034741:RNA, Small Interfering; D053218:Receptors, Death Domain; D053181:Caspase 8