The Bcl-w promoter is activated by beta-catenin/TCF4 in human colorectal carcinoma cells.
The antiapoptotic BCL-2 family protein BCL-W is often overexpressed in colorectal carcinoma (CRC) where it correlates with advanced stage and expression of p53. In this work we have analysed the Bcl-w promoter to identify potential regulators of BCL-W expression in CRC cells. The Bcl-w promoter was highly active in cell lines derived from CRC as well as other cancer types. Although expression of p53 and BCL-W correlate in CRC, overexpression of wild type or mutant p53 did not significantly alter Bcl-w promoter activity, and deletion of endogenous p53 did not alter the expression of Bcl-w RNA in HCT116 cells. Promoter deletion analysis lead to the identification of a potential binding site for TCF/LEF factors, obligate binding partners for beta-catenin, a downstream target of the WNT signalling pathway. TCF4 and beta-catenin interacted with the Bcl-w promoter in intact HCT116 cells and mutation of this site significantly decreased promoter activity. The activity of the Bcl-w promoter was increased or decreased, respectively, by overexpression of beta-catenin or dominant negative TCF4. beta-catenin is activated in the majority of CRC and these results suggest that BCL-W may function as a downstream effector of inappropriate WNT/beta-catenin signalling.
Lapham
Abigail
A
Cancer Research UK Clinical Centre, Cancer Sciences Division, University of Southampton School of Medicine, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK.
Adams
Jemimah E
JE
Paterson
Alex
A
Lee
Melanie
M
Brimmell
Matthew
M
Packham
Graham
G
D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001665:Binding Sites; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D003001:Cloning, Molecular; D015179:Colorectal Neoplasms / Q000235:genetics*; D019295:Computational Biology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012334:RNA, Neoplasm / Q000378:metabolism; D017384:Sequence Deletion; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C491073:BCL2L2 protein, human; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D012334:RNA, Neoplasm; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin