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

Abstract

Nuclear factor-κB (NF-κB) is constitutively activated in diverse human malignancies by mechanisms that are not understood1,2. The MUC1 oncoprotein is aberrantly overexpressed by most human carcinomas and, similarly to NF-κB, blocks apoptosis and induces transformation3,4,5,6. This study demonstrates that overexpression of MUC1 in human carcinoma cells is associated with constitutive activation of NF-κB p65. We show that MUC1 interacts with the high-molecular-weight IκB kinase (IKK) complex in vivo and that the MUC1 cytoplasmic domain binds directly to IKKβ and IKKγ. Interaction of MUC1 with both IKKβ and IKKγ is necessary for IKKβ activation, resulting in phosphorylation and degradation of IκBα. Studies in non-malignant epithelial cells show that MUC1 is recruited to the TNF-R1 complex and interacts with IKKβ–IKKγ in response to TNFα stimulation. TNFα-induced recruitment of MUC1 is dependent on TRADD and TRAF2, but not the death-domain kinase RIP1. In addition, MUC1-mediated activation of IKKβ is dependent on TAK1 and TAB2. These findings indicate that MUC1 is important for physiological activation of IKKβ and that overexpression of MUC1, as found in human cancers, confers sustained induction of the IKKβ–NF-κB p65 pathway.

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Figure 1: MUC1 targets NF-κB p65 to the nucleus by inducing phosphorylation and degradation of IκBα.
Figure 2: MUC1-CD binds directly to IKKβ and IKKγ.
Figure 3: MUC1 activates the IKKβ–IKKγ complex.
Figure 4: MUC1-C contributes to NF-κB activation in the response of MCF-10A cells to TNFα.
Figure 5: MUC1 is necessary for TNFα-induced recruitment of TAK1 to the TNF-R1 complex.

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Acknowledgements

This work was supported by Grant CA97098, CA42802 and CA100707 awarded by the National Cancer Institute (Bethesda, MD). The authors thank Michael Karin (University of California San Diego, CA) for the GST–IKKβ plasmid, Richard Gaynor (Lilly Research Laboratories, Indianapolis, IN) for the GST–IKKγ plasmid, and Al Baldwin (University of North Carolina, Chapel Hill, NC) for the wild-type and mutant pNF-κB-Luc reporters. Kamal Chauhan is acknowledged for technical support.

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Correspondence to Donald Kufe.

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Supplementary Figures S1, S2, S3, S4, S5 and S6 (PDF 657 kb)

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Ahmad, R., Raina, D., Trivedi, V. et al. MUC1 oncoprotein activates the IκB kinase β complex and constitutive NF-κB signalling. Nat Cell Biol 9, 1419–1427 (2007). https://doi.org/10.1038/ncb1661

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