Truncated APC regulates the transcriptional activity of -catenin in a cell cycle dependent manner

Author： Schneikert Jean Grohmann Annette Behrens Jrgen

ISSN： 1460-2083

Source： Human Molecular Genetics, Vol.16, Iss.2, 2007-01, pp. : 199-209

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Abstract

Most colon cancer cells express truncated versions of the tumour suppressor Adenomatous Polyposis Coli (APC). These molecules are selected during tumourigenesis for impaired -catenin degrading activity. In this study, we describe that truncated APC can still control the activity of -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 -catenin. Second, reduction of the levels of truncated APC by RNA interference increases the activity of a -catenin-dependent reporter gene and stimulates the expression of the -catenin target gene AXIN2/conductin. This occurs without alterations of the amounts of cytosolic -catenin. Conversely, ectopic expression of truncated APC decreases -catenin-dependent transcription without affecting the intensity of immunofluorescence staining of -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 -catenin bound to APC increases and the transcriptional activity of -catenin drops in an APC-dependent manner. Again, this occurs independently of the amounts of either total or phosphorylated cytosolic -catenin. Together, these results indicate that truncated APC controls the ability of -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 -catenin in a cell cycle-dependent manner.