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BMC Cancer. 2008 Jul 15;8:199. doi: 10.1186/1471-2407-8-199.

The function of BCL9 in Wnt/beta-catenin signaling and colorectal cancer cells.

Author information

1
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK. marcd@mrc-lmb.cam.ac.uk

Abstract

BACKGROUND:

Most cases of colorectal cancer are initiated by hyperactivation of the Wnt/beta-catenin pathway due to mutations in the APC tumour suppressor, or in beta-catenin itself. A recently discovered component of this pathway is Legless, which is essential for Wnt-induced transcription during Drosophila development. Limited functional information is available for its two mammalian relatives, BCL9 and B9L/BCL9-2: like Legless, these proteins bind to beta-catenin, and RNAi-mediated depletion of B9L/BCL9-2 has revealed that this protein is required for efficient beta-catenin-mediated transcription in mammalian cell lines. No loss-of-function data are available for BCL9.

METHODS:

We have used overexpression of dominant-negative forms of BCL9, and RNAi-mediated depletion, to study its function in human cell lines with elevated Wnt pathway activity, including colorectal cancer cells.

RESULTS:

We found that BCL9 is required for efficient beta-catenin-mediated transcription in Wnt-stimulated HEK 293 cells, and in the SW480 colorectal cancer cell line whose Wnt pathway is active due to APC mutation. Dominant-negative mutants of BCL9 indicated that its function depends not only on its beta-catenin ligand, but also on an unknown ligand of its C-terminus. Finally, we show that BCL9 and B9L are both Wnt-inducible genes, hyperexpressed in colorectal cancer cell lines, indicating that they are part of a positive feedback loop.

CONCLUSION:

BCL9 is required for efficient beta-catenin-mediated transcription in human cell lines whose Wnt pathway is active, including colorectal cancer cells, indicating its potential as a drug target in colorectal cancer.

PMID:
18627596
PMCID:
PMC2478683
DOI:
10.1186/1471-2407-8-199
[Indexed for MEDLINE]
Free PMC Article

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