Human Molecular Genetics Advance Access originally published online on December 22, 2006
Human Molecular Genetics 2007 16(2):199-209; doi:10.1093/hmg/ddl464
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Truncated APC regulates the transcriptional activity of ß-catenin in a cell cycle dependent manner
Nikolaus-Fiebiger-Center for Molecular Medicine, University Erlangen-Nürnberg, Glückstrasse 6, 91054 Erlangen, Germany
* To whom correspondence should be addressed. Tel: +49 91318529110; Fax: +49 91318529111; Email: jschneik{at}molmed.uni-erlangen.de
Received October 9, 2006; Revised November 28, 2006; Accepted December 8, 2006
Most colon cancer cells express truncated versions of the tumour suppressor Adenomatous Polyposis Coli (APC). These molecules are selected during tumourigenesis for impaired ß-catenin degrading activity. In this study, we describe that truncated APC can still control the activity of ß-catenin in colon cancer cell lines via its first 20 amino acid repeat. First, we show that both endogenous and ectopically expressed truncated APC molecules can bind to ß-catenin. Second, reduction of the levels of truncated APC by RNA interference increases the activity of a ß-catenin-dependent reporter gene and stimulates the expression of the ß-catenin target gene AXIN2/conductin. This occurs without alterations of the amounts of cytosolic ß-catenin. Conversely, ectopic expression of truncated APC decreases ß-catenin-dependent transcription without affecting the intensity of immunofluorescence staining of ß-catenin in transfected cells. Third, we reveal that the APC level increases when cells reach the G1-S boundary during cell cycle progression. Simultaneously, the amount of ß-catenin bound to APC increases and the transcriptional activity of ß-catenin drops in an APC-dependent manner. Again, this occurs independently of the amounts of either total or phosphorylated cytosolic ß-catenin. Together, these results indicate that truncated APC controls the ability of ß-catenin to activate transcription. As we also show that the inhibition involves the first 20 amino acid repeat of APC, our data suggest that colon cancer cells retain a truncated APC molecule containing at least the first 20 amino acid repeat to modulate the transcriptional activity of ß-catenin in a cell cycle-dependent manner.
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