APC (adenomatosis polyposis coli) is a human gene that is classified as a tumor suppressor gene. Tumor suppressor genes prevent the uncontrolled growth of cells that may result in cancerous tumors. The protein made by the APC gene plays a critical role in several cellular processes that determine whether a cell may develop into a tumor. The APC protein helps control how often a cell divides, how it attaches to other cells within a tissue, or whether a cell moves within or away from a tissue. This protein also helps ensure that the chromosome number in cells produced through cell division is correct. The APC protein accomplishes these tasks mainly through association with other proteins, especially those that are involved in cell attachment and signaling. The activity of one protein in particular, beta-catenin, is controlled by the APC protein (see: Wnt signaling pathway). Regulation of beta-catenin prevents genes that stimulate cell division from being turned on too often and prevents cell overgrowth.
The APC gene is located on the long (q) arm of chromosome 5 between positions 21 and 22, from base pair 112,118,468 to base pair 112,209,532.
Familial adenomatous polyposis
(FAP) is caused by mutations in the APC gene. More than 800 mutations
in the APC gene have been identified in families with classic and attenuated types of familial adenomatous polyposis. Most of these mutations cause the production of an APC protein that is abnormally short and nonfunctional. This short protein cannot suppress the cellular overgrowth that leads to the formation of polyps, which can become cancerous. The most common mutation in familial adenomatous polyposis is a deletion of five bases (the building blocks of DNA) in the APC gene. This mutation changes the sequence of amino acids (the building material of proteins) in the resulting APC protein beginning at position 1309.
Another mutation is carried by approximately 6 percent of people of Ashkenazi (eastern and central European) Jewish heritage. This mutation results in the substitution of the amino acid lysine for isoleucine at position 1307 in the APC protein (also written as I1307K or Ile1307Lys). This change was initially thought to be harmless, but has recently been shown to be associated with a 10 to 20 percent increased risk of colon cancer.
Regulation of Proliferation
The (Adenomatosis Polyposis Coli) APC protein normally builds a complex with glycogensynthasekinase 3beta(GSK 3β) and Axin via interactions with the 20AA and SAMP repeats. This complex is then able to bind β- catenins in the cytoplasm, that have dissociated from adherens contacts between cells. With the help of Casein Kinase 1 (CK1) which does the first phosphorylation of β-catenin
, there is subsequent phosphorylation by GSK-3β. This targets β-catenin for ubuiquitination and degradation by cellular proteosomes. This prevents it from translocating into the nucleus, where it acts as a transcription factor for proliferation genes. APC is also thought to be targeted to microtubules
via the PDZ binding domain, stabilising them. The deactivation of the APC protein can take place after certain chain reactions in the cytoplasm are started, e.g. through the Wnt signals that destroy the conformation of the complex. In the nucleus it complexes with legless/BCL9, TCF, and Pygo and begins function of an RNA polymerase but for oncogenes.
Mutations in APC often occur early on in cancers such as colon cancer. Patients with familial adenomatous polyposis
(FAP) have germline mutations, with 95% being nonsense/frameshift mutations leading to premature stop codons. 33% of mutations occur between amino acids 1061-1309. In somatic mutations, over 60% occur within a mutation cluster region (1286-1513), causing loss of axin binding sites in all but 1 of the 20AA repeats. Mutations in APC lead to loss of β-catenin regulation, altered cell migration and chromosome instability.
Rosenberg et al.
found that APC directs cholinergic synapse assembly between neurons, a finding with implications for autonomic neuropathies, for Alzheimer's disease, for age-related hearing loss, and for some forms of epilepsy and schizophrenia.
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