APC Gene Function

FAP, or Familial Adenomatous Polyposis, is a genetically inherited form of colon cancer that results from a non-functional protein product of the APC (Adenomatous Polyposis Coli) gene.  This gene functions within many facets of cell biology including cell adhesion and cellular structure, as well as various aspects of cell meiosis (division) such as spindle formation and chromosome segregation.  However, these functions are not critical for understanding APC's function in FAP disease development.

3-D Representation of APC protein from Protein Workshop

You see, APC has been long-identified as a "tumor-suppressor gene," but, in reality, is acts as a suppressor of an early-initiating event of tumorigenesis (the beginnings of tumor formation) by maintaining low levels of a molecule called beta-catenin in the cell's nucleus.  The functional APC protein product interacts with Axin and GSK3 to form what biologists call a "destruction complex."  When these three proteins oligomerize, or loosely bind to one another, a site forms where interactions between Axin and GSK3 (plus an input of cellular energy, or ATP) mark beta-catenin for degradation by the proteosome.  This action leaves nuclear levels of beta-catenin very low, which keeps the Wnt signaling pathway suppressed.  It is suspected that stabilized levels of beta-catenin in the nucleus acts as an early event during, and may even initiate, tumorigenesis of adenomatous polyps in the intestinal epithelium.  When beta-catenin levels are stable in the cytoplasm, there is plenty of opportunity for its translocation into the cell's nucleus where it interacts with TCF (T-cell factor) and LEF (lymphoid-enhancer factor) to activate transcription within the nucleus.  This TCF and LEF-induced transcription has been described to have stem cell-like properties, where the DNA is rapidly and repetitively replicated.  These events are currently thought to be involved in the earliest steps of cancerous tumor formation (tumorigenesis).

Since APC is such a critical protein that functions in nearly all bodily tissues, it has no repressor domains.  However, two promoters have been identified within the APC gene; they are known as promoters 1A and 1B.  The addition of methyl groups to DNA nucleotides within these promoter regions results in decreased expression of the APC gene, thus fewer APC proteins are made.  There is also a site, called a 5' CCAAT box, which is recognized by a CCAAT Binding Factor (CBF), and the recognition of this site by a CBF results in a great increase in the amount of APC protein product produced. Conversely, when the region surrounding the CCAAT box is methylated, CBFs cannot recognize their binding region and smaller amounts of the protein product are made (usually, in genetics, methylation of genes results in less expression).