MUC1-C ONCOPROTEIN FUNCTIONS AS A DIRECT ACTIVATOR OF THE NF-κB p65 TRANSCRIPTION FACTOR

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 17; pp. 7013 - 7021
• Main Authors: Ahmad, Rehan, Raina, Deepak, Joshi, Maya Datt, Kawano, Takeshi, Ren, Jian, Kharbanda, Surender, Kufe, Donald
• Format: Journal Article
• Language: English
• Published: 25.08.2009
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-0523

Nuclear factor- κ B (NF- κ B) is constitutively activated in diverse human malignancies. The MUC1 oncoprotein is overexpressed in human carcinomas and, like NF- κ B, blocks cell death and induces transformation. The present studies demonstrate that MUC1 constitutively associates with NF- κ B p65 in carcinoma cells. The MUC1 C-terminal subunit (MUC1-C) cytoplasmic domain binds directly to NF- κ B p65 and, importantly, blocks the interaction between NF- κ B p65 and its inhibitor I κ B α . We show that NF- κ B p65 and MUC1-C constitutively occupy the promoter of the Bcl-xL gene in carcinoma cells and that MUC1-C contributes to NF- κ B-mediated transcriptional activation. Studies in non-malignant epithelial cells show that MUC1-C interacts with NF- κ B in the response to TNF α stimulation. Moreover, TNF α induces the recruitment of NF- κ B p65-MUC1-C complexes to NF- κ B target genes, including the promoter of the MUC1 gene itself. We also show that a small peptide inhibitor of MUC1-C oligomerization blocks the interaction with NF- κ B p65 in vitro and in cells. The MUC1-C inhibitor decreases MUC1-C and NF- κ B p65 promoter occupancy and expression of NF- κ B target genes. These findings indicate that MUC1-C is a direct activator of NF- κ B p65 and that an inhibitor of MUC1 function is effective in blocking activation of the NF- κ B pathway.