MUC1-C oncoprotein induces TCF7L2 transcription factor activation and promotes cyclin D1 expression in human breast cancer cells.
MUC1 is a heterodimeric glycoprotein that is overexpressed in breast cancers. The present studies demonstrate that the oncogenic MUC1 C-terminal subunit (MUC1-C) associates with the TCF7L2 transcription factor. The MUC1-C cytoplasmic domain (MUC1-CD) binds directly to the TCF7L2 C-terminal region. MUC1-C blocks the interaction between TCF7L2 and the C-terminal-binding protein (CtBP), a suppressor of TCF7L2-mediated transcription. TCF7L2 and MUC1-C form a complex on the cyclin D1 gene promoter and MUC1-C promotes TCF7L2-mediated transcription by the recruitment of β-catenin and p300. Silencing MUC1-C in human breast cancer cells down-regulated activation of the cyclin D1 promoter and decreased cyclin D1 expression. In addition, a MUC1-C inhibitor blocked the interaction with TCF7L2 and suppressed cyclin D1 levels. These findings indicate that the MUC1-C oncoprotein contributes to TCF7L2 activation and thereby promotes cyclin D1 expression in breast cancer cells.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
Hasan
H
Rajabi
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
Rehan
R
Ahmad
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
Caining
C
Jin
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
Michio
M
Kosugi
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
Maroof
M
Alam
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
Maya Datt
MD
Joshi
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115. Electronic address: donald_kufe@dfci.harvard.edu.
Donald
D
Kufe
D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism
C530104:CCND1 protein, human; D004268:DNA-Binding Proteins; C060192:MUC1 protein, human; D018396:Mucin-1; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin; D019938:Cyclin D1; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; D050880:p300-CBP Transcription Factors