MUC1-C oncoprotein functions as a direct activator of the nuclear factor-kappaB p65 transcription factor.
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.
Ahmad
Rehan
R
Dana-Farber Cancer Institute, Harvard Medical School and Genus Oncology, Boston, Massachusetts 02115, USA.
Raina
Deepak
D
Joshi
Maya Datt
MD
Kawano
Takeshi
T
Ren
Jian
J
Kharbanda
Surender
S
Kufe
Donald
D
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
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
FEBS Lett. 1994 Dec 12;356(1):130-6
7988707
Oncogene. 2006 Oct 30;25(51):6781-99
17072328
J Biol Chem. 2007 Jul 6;282(27):19321-30
17500061
Cancer Res. 2005 Nov 15;65(22):10413-22
16288032
Cell. 2003 Jul 25;114(2):181-90
12887920
EMBO J. 2006 Aug 23;25(16):3774-83
16888623
Annu Rev Immunol. 1998;16:225-60
9597130
Immunity. 2004 Sep;21(3):415-28
15357952
J Biol Chem. 2001 Sep 21;276(38):35239-42
11483589
J Biol Chem. 2001 Mar 2;276(9):6061-4
11152665
Mol Cell. 2007 Sep 21;27(6):992-1004
17889671
Nat Rev Mol Cell Biol. 2004 May;5(5):392-401
15122352
J Cell Biochem. 2002;86(4):759-72
12210742
Cell. 1998 Dec 11;95(6):759-70
9865694
Oncogene. 2006 Oct 30;25(51):6706-16
17072323
J Biol Chem. 2004 Oct 29;279(44):45721-7
15322085
Nat Cell Biol. 2007 Dec;9(12):1419-27
18037881
Mol Cell. 2006 Jan 20;21(2):295-305
16427018
Cancer Cell. 2004 Feb;5(2):163-75
14998492
Cell Death Differ. 2006 May;13(5):861-72
16470223
Cancer Res. 2008 Aug 1;68(15):6136-44
18676836
Cancer Res. 1990 Sep 15;50(18):6075-86
1975513
Nat Immunol. 2002 Mar;3(3):221-7
11875461
J Biol Chem. 2003 Sep 12;278(37):35458-64
12826677
J Biol Chem. 2007 Jan 5;282(1):257-66
17102128
J Biol Chem. 2004 May 14;279(20):20607-12
14999001
Oncogene. 1999 Nov 22;18(49):6845-52
10602460
Nat Cell Biol. 2001 Sep;3(9):785-92
11533657
Oncogene. 2003 Sep 4;22(38):6107-10
12955090
Cell. 1998 Dec 11;95(6):749-58
9865693
Mol Cancer Res. 2006 Jul;4(7):489-97
16849524
Med Res Rev. 2007 Nov;27(6):755-95
17019680
Nat Immunol. 2005 May;6(5):439-45
15843800
Cancer Res. 2009 Jun 15;69(12):5133-41
19491255
Hybridoma. 1984 Fall;3(3):223-32
6094338
Cell. 2008 Feb 8;132(3):344-62
18267068
J Immunol. 1997 May 15;158(10):4750-7
9144489
Mol Cell Biol. 1998 Dec;18(12):7216-24
9819408