Адамның APC гені: Колоректальды қатер және мутациялар

Protein coding gene in the species Homo sapiens
the tumor suppressor APC, in which mutations lead to colon cancer

Adenomatous polyposis coli (APC) also known as deleted in polyposis 2.5 (DP2.5) is a protein that in humans is encoded by the APC gene. The APC protein is a negative regulator that controls beta catenin concentrations and interacts with E cadherin, which are involved in cell adhesion. Mutations in the APC gene may result in colorectal cancer and desmoid tumors. or whether a cell moves within or away from 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 human APC gene is located on the long (q) arm of chromosome 5 in band q22.2 (5q22.2). The APC gene has been shown to contain an internal ribosome entry site. APC orthologs have also been identified in all mammals for which complete genome data are available.

The full length human protein comprises 2,843 amino acids with a (predicted) molecular mass of 311646 Da. Several N terminal domains have been structurally elucidated in unique atomistic high resolution complex structures. Most of the protein is predicted to be intrinsically disordered. It is not known if this large predicted unstructured region from amino acid 800 to 2843 persists in vivo or would form stabilised complexes – possibly with yet unidentified interacting proteins. Recently, it has been experimentally confirmed that the mutation cluster region around the center of APC is intrinsically disordered in vitro.

The most common mutation in colon cancer is inactivation of APC. In absence of APC inactivating mutations, colon cancers commonly carry activating mutations in beta catenin or inactivating mutations in RNF43. 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 presumably 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 in the APC gene. This mutation changes the sequence of amino acids in the resulting APC protein beginning at position 1309. Mutations in the APC gene have also been found to lead to the development of desmoid tumors in FAP patients. 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 has been shown to be associated with an increased risk of colon cancer, with moderate effect size. APC I1307K has also been implicated as a risk factor for certain other cancers. APC is also thought to be targeted to microtubules via the PDZ binding domain, stabilizing 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. The ability of APC to bind β catenin has been classically considered to be an integral part of the protein's mechanistic function in the destruction complex, along with binding to Axin through the SAMP repeats. These models have been substantiated by observations that common APC loss of function mutations in the mutation cluster region often remove several β catenin binding sites and SAMP repeats. However, recent evidence from Yamulla and colleagues have directly tested those models and imply that APC's core mechanistic functions may not require direct binding to β catenin, but necessitate interactions with Axin. The researchers hypothesized that APC's many β catenin binding sites increase the protein's efficiency at destroying β catenin, yet are not absolutely necessary for the protein's mechanistic function. Further research is clearly necessary to elucidate the precise mechanistic function of APC in the destruction complex.

Mutations in APC often occur early on in cancers such as colon cancer.

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. (29)