title: MUC1-C oncoprotein functions as a direct activator of the nuclear factor-kappaB p65 transcription factor.
abstract: Nuclear factor-kappaB (NF-kappaB) is constitutively activated in diverse human malignancies. The mucin 1 (MUC1) oncoprotein is overexpressed in human carcinomas and, like NF-kappaB, blocks cell death and induces transformation. The present studies show that MUC1 constitutively associates with NF-kappaB p65 in carcinoma cells. The MUC1 COOH-terminal subunit (MUC1-C) cytoplasmic domain binds directly to NF-kappaB p65 and, importantly, blocks the interaction between NF-kappaB p65 and its inhibitor IkappaBalpha. We show that NF-kappaB p65 and MUC1-C constitutively occupy the promoter of the Bcl-xL gene in carcinoma cells and that MUC1-C contributes to NF-kappaB-mediated transcriptional activation. Studies in nonmalignant epithelial cells show that MUC1-C interacts with NF-kappaB in the response to tumor necrosis factor-alpha stimulation. Moreover, tumor necrosis factor-alpha induces the recruitment of NF-kappaB p65-MUC1-C complexes to NF-kappaB 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-kappaB p65 in vitro and in cells. The MUC1-C inhibitor decreases MUC1-C and NF-kappaB p65 promoter occupancy and expression of NF-kappaB target genes. These findings indicate that MUC1-C is a direct activator of NF-kappaB p65 and that an inhibitor of MUC1 function is effective in blocking activation of the NF-kappaB pathway.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School and Genus Oncology, Boston, Massachusetts 02115, USA.
authors.forename: Rehan
authors.initials: R
authors.lastname: Ahmad
authors.forename: Deepak
authors.initials: D
authors.lastname: Raina
authors.forename: Maya Datt
authors.initials: MD
authors.lastname: Joshi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawano
authors.forename: Jian
authors.initials: J
authors.lastname: Ren
authors.forename: Surender
authors.initials: S
authors.lastname: Kharbanda
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
mesh_terms: D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D018396:Mucin-1 / Q000235:genetics* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020298:U937 Cells; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; D020672:I-kappa B Proteins; C060192:MUC1 protein, human; D018396:Mucin-1; C000606204:NFKBIA protein, human; D021122:Protein Subunits; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D000072000:NF-KappaB Inhibitor alpha
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