World Library  
Flag as Inappropriate
Email this Article

Adenomatosis polyposis coli

Article Id: WHEBN0028057463
Reproduction Date:

Title: Adenomatosis polyposis coli  
Author: World Heritage Encyclopedia
Language: English
Subject: Chromosome 5 (human), Nucleolus organizer region, Deleted in Colorectal Cancer
Collection:
Publisher: World Heritage Encyclopedia
Publication
Date:
 

Adenomatosis polyposis coli

Adenomatous polyposis coli
PDB rendering based on 1deb.
Available structures
PDB Ortholog search: RCSB
Identifiers
APC Gene
RNA expression pattern

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.[1] Mutations in the APC gene may result in colorectal cancer.[2]

APC 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 human APC gene is located on the long (q) arm of chromosome 5 in band q22.2 The APC gene has been shown to contain an internal ribosome entry site. APC orthologs[3] have also been identified in all mammals for which complete genome data are available.

Structure

The full-length human protein comprises 2843 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 unindentified interacting proteins.[4] Recently, it has been experimentally confirmed that the mutation cluster region around the center of APC is intrinsically disordered in vitro.[5]

Role in cancer

The most common mutation in colon cancer is inactivation of APC. When APC does not have an inactivating mutation, Frequently there are activating mutations in beta catenin. Mutations in APC can be inherited, or arise sporadically in the somatic cells, often as the result of mutations in other genes that result in the inability to repair mutations in the DNA. In order for cancer to develop, both alleles (copies of the APC gene) must be mutated. Mutations in APC or β-catenin must be followed by other mutations to become cancerous; however, in carriers of an APC inactivating mutations, the risk of colorectal cancer by age 40 is almost 100%.[2]

Familial adenomatous polyposis (FAP) is caused by an inherited, inactivating mutation 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 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.

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 (Adenomatous Polyposis Coli) APC protein normally builds a complex with glycogen synthase kinase 3-beta( GSK-3β) and axin via interactions with the 20 AA 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 carries out an initial phosphorylation of β-catenin, GSK-3β is able to phosphorylate β-catenin a second time. This targets β-catenin for ubiquitination 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, 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 and begins function of an RNA polymerase but for oncogenes.

Mutations

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.

Neurological role

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.

Interactions

APC (gene) has been shown to interact with

[27]

See also

References

Further reading

External links

  • GeneReviews/NCBI/NIH/UW entry on APC-Associated Polyposis Conditions
  • OMIM entries on APC-Associated Polyposis Conditions
  • Medical Subject Headings (MeSH)
  • GeneCard
  • )

This article was sourced from Creative Commons Attribution-ShareAlike License; additional terms may apply. World Heritage Encyclopedia content is assembled from numerous content providers, Open Access Publishing, and in compliance with The Fair Access to Science and Technology Research Act (FASTR), Wikimedia Foundation, Inc., Public Library of Science, The Encyclopedia of Life, Open Book Publishers (OBP), PubMed, U.S. National Library of Medicine, National Center for Biotechnology Information, U.S. National Library of Medicine, National Institutes of Health (NIH), U.S. Department of Health & Human Services, and USA.gov, which sources content from all federal, state, local, tribal, and territorial government publication portals (.gov, .mil, .edu). Funding for USA.gov and content contributors is made possible from the U.S. Congress, E-Government Act of 2002.
 
Crowd sourced content that is contributed to World Heritage Encyclopedia is peer reviewed and edited by our editorial staff to ensure quality scholarly research articles.
 
By using this site, you agree to the Terms of Use and Privacy Policy. World Heritage Encyclopedia™ is a registered trademark of the World Public Library Association, a non-profit organization.
 



Copyright © World Library Foundation. All rights reserved. eBooks from World eBook Library are sponsored by the World Library Foundation,
a 501c(4) Member's Support Non-Profit Organization, and is NOT affiliated with any governmental agency or department.