APC (gene)
Encyclopedia
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
. Mutations in the APC gene may result in colorectal cancer
.
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
between positions 21 and 22, from base pair
112,118,468 to base pair 112,209,532. 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 2843 amino acids with a (predicted) molecular mass of 311646 Da. Most domains of this protein are solved structurally and exhibit high intrinsic disorder and flexibility as a monomer, and a low content of stable secondary structure. Thus it is a member of the intrinsically unstructured proteins
. Little is known about the in vivo full-length unfolded protein.
Familial adenomatous polyposis
(FAP) is caused by mutations in the APC gene. More than 800 mutation
s 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 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.
) 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.
(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.
with
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the APC gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. Mutations in the APC gene may result in colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
.
APC is classified as a tumor suppressor gene
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
. 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
Beta-catenin
Beta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...
, is controlled by the APC protein (see: Wnt signaling pathway
Wnt signaling pathway
The Wnt signaling pathway is a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.-Discovery:...
). 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
Chromosome 5 (human)
Chromosome 5 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 5 spans about 181 million base pairs and represents almost 6% of the total DNA in cells. Chromosome 5 is one of the largest human chromosomes, yet has one of the lowest gene...
between positions 21 and 22, from base pair
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
112,118,468 to base pair 112,209,532. 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 2843 amino acids with a (predicted) molecular mass of 311646 Da. Most domains of this protein are solved structurally and exhibit high intrinsic disorder and flexibility as a monomer, and a low content of stable secondary structure. Thus it is a member of the intrinsically unstructured proteins
Intrinsically unstructured proteins
Intrinsically unstructured proteins, often referred to as naturally unfolded proteins or disordered proteins, are proteins characterized by lack of stable tertiary structure when the protein exists as an isolated polypeptide chain under physiological conditions in vitro...
. Little is known about the in vivo full-length unfolded protein.
Role in cancer
The most common mutation in colon cancer is inactivation of APC. When APC does not have an inactivating mutation, beta catenin does. These mutations can be inherited, or arise sporadically, often as the result of mutations in other genes that produce chromosomal instability. A mutation on 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%.Familial adenomatous polyposis
Familial adenomatous polyposis
Familial adenomatous polyposis is an inherited condition in which numerous polyps form mainly in the epithelium of the large intestine. While these polyps start out benign, malignant transformation into colon cancer occurs when not treated....
(FAP) is caused by mutations in the APC gene. More than 800 mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s 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 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
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
for isoleucine
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....
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-3βGSK3B
Glycogen synthase kinase 3 beta, also known as GSK3B, is an enzyme that in humans is encoded by the GSK3B gene.- Function :Glycogen synthase kinase-3 is a proline-directed serine-threonine kinase that was initially identified as a phosphorylating and inactivating glycogen synthase. Two isoforms,...
) and axin
AXIN1
Axin-1 is a protein that in humans is encoded by the AXIN1 gene.-Interactions:AXIN1 has been shown to interact with Beta-catenin, GSK3B, TSC2, APC, LRP5, DVL1, MAP3K1, CSNK1E, Casein kinase 1, alpha 1 and PPP2R5A.-Further reading:...
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
Casein kinase 1
The Casein kinase 1 family of protein kinases are serine/threonine-selective enzymes that function as regulators of signal transduction pathways in most eukaryotic cell types...
), 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
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
and degradation by cellular proteosomes. This prevents it from translocating
Protein targeting
Protein targeting or protein sorting is the mechanism by which a cell transports proteins to the appropriate positions in the cell or outside of it. Sorting targets can be the inner space of an organelle, any of several interior membranes, the cell's outer membrane, or its exterior via secretion...
into the nucleus, where it acts as a transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
for proliferation genes. APC is also thought to be targeted to microtubules via the PDZ binding domain
PDZ domain
The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals...
, 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
BCL9
B-cell CLL/lymphoma 9 protein is a protein that in humans is encoded by the BCL9 gene.Common variations in the BCL9 gene, which is in the distal area, confer risk of schizophrenia and may also be associated with bipolar disorder and major depressive disorder. -Further reading:...
, TCF
TCF7
Transcription factor 7 is a protein that in humans is encoded by the TCF7 gene.-Further reading:...
, and Pygo
PYGO2
Pygopus homolog 2 is a protein that in humans is encoded by the PYGO2 gene.-Further reading:...
and begins function of an RNA polymerase
RNA polymerase
RNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...
but for oncogenes.
Mutations
Mutations in APC often occur early on in cancers such as colon cancer. Patients with familial adenomatous polyposisFamilial adenomatous polyposis
Familial adenomatous polyposis is an inherited condition in which numerous polyps form mainly in the epithelium of the large intestine. While these polyps start out benign, malignant transformation into colon cancer occurs when not treated....
(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 interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with
- ARHGEF4ARHGEF4Rho guanine nucleotide exchange factor 4 is a protein that in humans is encoded by the ARHGEF4 gene.-Interactions:ARHGEF4 has been shown to interact with APC.-Further reading:...
, - AXIN1AXIN1Axin-1 is a protein that in humans is encoded by the AXIN1 gene.-Interactions:AXIN1 has been shown to interact with Beta-catenin, GSK3B, TSC2, APC, LRP5, DVL1, MAP3K1, CSNK1E, Casein kinase 1, alpha 1 and PPP2R5A.-Further reading:...
, - BUB1BUB1Mitotic checkpoint serine/threonine-protein kinase BUB1 also known as BUB1 is an enzyme that in humans is encoded by the BUB1 gene....
, - CTNNB1Beta-cateninBeta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...
, - CSNK2BCSNK2BCasein kinase, a ubiquitous, well-conserved protein kinase involved in cell metabolism and differentiation, is characterised by its preference for Serine or Threonine in acidic stretches of amino acids. The enzyme is a tetramer of 2 alpha- and 2 beta-subunits...
, - CSNK2A1,
- CTNNA1,
- DLG3DLG3Disks large homolog 3 also known as neuroendocrine-DLG or synapse-associated protein 102 is a protein that in humans is encoded by the DLG3 gene...
, - KIFAP3KIFAP3Kinesin-associated protein 3 is a protein that in humans is encoded by the KIFAP3 gene. It is a non-motor, accesssory subunit which co-oligomerizes with the motor subunits KIF3A and KIF3B or KIF3C, to form heterotrimeric kinesin-2 motor proteins...
, - MAPRE2MAPRE2Microtubule-associated protein RP/EB family member 2 is a protein that in humans is encoded by the MAPRE2 gene.-Interactions:MAPRE2 has been shown to interact with APC.-Further reading:...
, - JUPPlakoglobinJunction plakoglobin, also known as gamma-catenin or JUP, is a protein that in humans is encoded by the JUP gene.- Function :...
, - SIAH1SIAH1E3 ubiquitin-protein ligase SIAH1 is an enzyme that in humans is encoded by the SIAH1 gene.-Interactions:SIAH1 has been shown to interact with PEG10, CACYBP, POU2AF1, RBBP8, BAG1, TRIB3, NUMB, KIF22, KHDRBS3, PEG3 and APC.-References:...
, - TFAP2ATFAP2ATranscription factor AP-2 alpha , also known as TFAP2A, is a protein that in humans is encoded by the TFAP2A gene.- Function :...
, - TUBA4ATUBA4ATubulin alpha-4A chain is a protein that in humans is encoded by the TUBA4A gene.-Interactions:TUBA4A has been shown to interact with NCOA6 and APC.-Further reading:...
, and - XPO1XPO1Exportin-1 is a protein that in humans is encoded by the XPO1 gene.-Interactions:XPO1 has been shown to interact with NMD3, CIITA, RANBP3, Nucleoporin 62, Ran, RANBP1, APC, SMARCB1 and CDKN1B.-Further reading:...
.
External Links
- GeneReviews/NCBI/NIH/UW entry on APC-Associated Polyposis Conditions
- OMIM entries on APC-Associated Polyposis Conditions
- GeneCard
- http://tools.niehs.nih.gov/gac/datamining/index.cfmDatabase concerning peer-reviewed reports on cancer critical alteration in several genes including (APC (protein)), (TP53), (β-cateninBeta-cateninBeta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...
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