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MUC1-C Oncoprotein Functions as a Direct Activator of the Nuclear Factor-B p65 Transcription Factor

¹ Dana-Farber Cancer Institute, Harvard Medical School and ² Genus Oncology, Boston, Massachusetts

Requests for reprints: Donald Kufe, Dana-Farber Cancer Institute, 44 Binney Street, Dana 830, Boston, MA 02115. Phone: 617-632-3141; Fax: 617-632-2934; E-mail: Donald_Kufe{at}dfci.harvard.edu.

Key Words: MUC1 • NF-B • IB • transactivation • targeted drugs

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

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