Data from MUC1-C Oncoprotein Functions as a Direct Activator of the Nuclear Factor-κB p65 Transcription Factor

Nuclear factor-κB (NF-κB) is constitutively activated in diverse human malignancies. The mucin 1 (MUC1) oncoprotein is overexpressed in human carcinomas and, like NF-κB, blocks cell death and induces transformation. The present studies show that MUC1 constitutively associates with NF-κB p65 in carcinoma cells. The MUC1 COOH-terminal subunit (MUC1-C) cytoplasmic domain binds directly to NF-κB p65 and, importantly, blocks the interaction between NF-κB p65 and its inhibitor IκBα. We show that NF-κB p65 and MUC1-C constitutively occupy the promoter of the Bcl-xL gene in carcinoma cells and that MUC1-C contributes to NF-κB–mediated transcriptional activation. Studies in nonmalignant epithelial cells show that MUC1-C interacts with NF-κB in the response to tumor necrosis factor-α stimulation. Moreover, tumor necrosis factor-α induces the recruitment of NF-κB p65-MUC1-C complexes to NF-κB target genes, including the promoter of the MUC1 gene itself. We also show that an inhibitor of MUC1-C oligomerization blocks the interaction with NF-κB p65 in vitro and in cells. The MUC1-C inhibitor decreases MUC1-C and NF-κB p65 promoter occupancy and expression of NF-κB target genes. These findings indicate that MUC1-C is a direct activator of NF-κB p65 and that an inhibitor of MUC1 function is effective in blocking activation of the NF-κB pathway. [Cancer Res 2009;69(17):7013–21]