MUC1 oncoprotein activates the IκB kinase β complex and constitutive NF-κB signalling

Nuclear factor-kappa B ( NF-kappa B) is constitutively activated in diverse human malignancies by mechanisms that are not understood(1,2). The MUC1 oncoprotein is aberrantly overexpressed by most human carcinomas and, similarly to NF-kappa B, blocks apoptosis and induces transformation(3-6). This study demonstrates that overexpression of MUC1 in human carcinoma cells is associated with constitutive activation of NF-kappa B p65. We show that MUC1 interacts with the high-molecular-weight I kappa B kinase (IKK) complex in vivo and that the MUC1 cytoplasmic domain binds directly to IKK beta and IKK gamma. Interaction of MUC1 with both IKK beta and IKK gamma is necessary for IKK beta activation, resulting in phosphorylation and degradation of I kappa B alpha. Studies in non-malignant epithelial cells show that MUC1 is recruited to the TNF-R1 complex and interacts with IKK eta-IKK gamma in response to TNF alpha stimulation. TNF alpha-induced recruitment of MUC1 is dependent on TRADD and TRAF2, but not the death-domain kinase RIP1. In addition, MUC1-mediated activation of IKK beta is dependent on TAK1 and TAB2. These findings indicate that MUC1 is important for physiological activation of IKK beta and that overexpression of MUC1, as found in human cancers, confers sustained induction of the IKK beta-NF kappa B p65 pathway.