APC (adenomatous polyposis coli)

Identity

Hugo	APC
Location	5q21
	APC (5q21) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are welcome : contact rocchi@biologia.uniba.it

DNA/RNA

Description	15 exons (with a particularly large 15th exon).
Transcription	9.0 kb mRNA; 8538 bp open reading frame.

Protein

Description	2843 amino acids; 310 kDa.
Function	APC is a classical tumour suppressor protein. The APC gene product indirectly regulates transcription of a number of critical cell proliferation genes, through its interaction with the transcription factor beta catenin. APC binding to beta catenin leads to ubiquitin-mediated beta catenin destruction; loss of APC function increases transcription of beta catenin targets. These targets include cyclin D, C-myc, ephrins and caspases. APC also interacts with numerous actin and microtubule associated proteins. APC itself stabilizes microtubules. Homozygous APC truncation has been shown to affect chromosome attachment in cultured cells. Roles for APC in cell migration have been demonstrated in vitro and in mouse models.
Homology	A second family member, APC2, is located on 19p13.3 (see non-annotated genes).

Mutations

Germinal

Germline mutations of APC cause a spectrum of diseases under the broad category of familial adenomatous polyposis (FAP). Mutations typically cluster in or just distal to the armadillo repeat region and truncate the protein near its middle. It is not known which is pathophysiologic - absence of the full-length protein or presence of the truncated version; evidence exists for both. The second hit creates another truncation or gene deletion. There is some evidence that the position of the first hit in the gene determines the pattern of the second hit. Rare hypomorphic mutations cause attenuated polyposis.

Somatic

Both copies of the APC gene are mutated in 80% of sporadic colorectal tumours.

Implicated in

Entity	Familial Adenomatous Polyposis (FAP)
Disease	Autosomal dominant disease in which patients develop thousands of colonic polyps during childhood and adolescence. Many of these will progress to cancers if not removed. FAP encompasses other disease syndromes with extra-colonic manifestations. In Gardner Syndrome, patients may develop the following extra-intestinal manifestations: Gastric and duodenal malignancies Cancer of the pancreas, biliary tree, and gallbladder. Hepatoblastoma. Congenital hypertrophy of the retinal pigment epithelium (CHRPE), a benign hyperpigmentation beneath the retina that is typically asymptomatic. , a tumor of the connective tissue that can cause morbidity and mortality by impinging on adjacent structures. DISEASE Osteomas and dental abnormalities. Epidermoid cysts and other skin abnormalities. In a subset of patients with Turcot's syndrome, intestinal polyposis due to APC mutation is associated with brain tumors, especially meduloblastoma.
Prognosis	Without treatment, the life expectancy is in the early 40s due to colon cancer. Treatment consists of regular screening, with polypectomy of large lesions. Due to the large number of polyps, eventual complete colectomy with or without proctosigmoidectomy is needed. Regular use of the cyclooxygenase inhibitor Sulindac and possibly other member of this class of drugs reduces the number of polyps. About ten percent of patients also experience significant morbidity from desmoid tumors.
Entity	Sporadic colorectal cancer.
Disease	Somatic mutation of the APC gene is found in the majority of colorectal adenocarcinomas. Sporadic colorectal cancer is the third most frequent cancer in the world.
Prognosis	The prognosis depends on the stage of the disease. Stage I lesions are usually cured by surgery . There is controversy about the use of chemotherapy in Stage II disease. In Stage III disease, chemotherapy improves the five year survival from ~50% to ~60%.
Oncogenesis	Loss of normal APC function is known to be an early event in both familial and sporadic colon cancer pathogenesis, occurring at the pre-adenoma stage. Current discussion is focused on whether loss of APC function precedes, follows, or is entwined with chromosomal instability. Later events include abnormalities of K-ras and p53. Generally colon cancers show either chromosomal instability (CIN), which correlates with loss of APC function, or microsatellite instability (MIN), which correlates with loss of mismatch repair function, but not both.

External links

	Nomenclature
Hugo	APC
GDB	APC
Entrez_Gene	APC  324  adenomatous polyposis coli
	Cards
Atlas	APC118
GeneCards	APC
Ensembl	APC [Search_View]   ENSG00000134982 [Gene_View]
Genatlas	APC
GeneLynx	APC
eGenome	APC
euGene	324
	Genomic and cartography
GoldenPath	APC  -  5q21   chr5:112101483-112209834 +  5q21-q22   [Description]    (hg18-Mar_2006)
Ensembl	APC - 5q21-q22 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	APC
	Gene and transcription
Genbank	AB210001 [ ENTREZ ]
Genbank	AF038181 [ ENTREZ ]
Genbank	AI492038 [ ENTREZ ]
Genbank	BC034955 [ ENTREZ ]
Genbank	BC056268 [ ENTREZ ]
RefSeq	NM_000038 [ SRS ]    NM_000038 [ ENTREZ ]
RefSeq	AC_000048 [ SRS ]    AC_000048 [ ENTREZ ]
RefSeq	NC_000005 [ SRS ]    NC_000005 [ ENTREZ ]
RefSeq	NT_034772 [ SRS ]    NT_034772 [ ENTREZ ]
RefSeq	NW_922751 [ SRS ]    NW_922751 [ ENTREZ ]
AceView	APC AceView - NCBI
Unigene	Hs.158932 [ SRS ]    Hs.158932 [ NCBI ]     HS158932 [ spliceNest ]
Fast-db	8297 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	P25054 [ SRS]    P25054 [ EXPASY ]     P25054 [ INTERPRO ]
Prosite	PS50176 ARM_REPEAT [ SRS ]    PS50176 ARM_REPEAT [ Expasy ]
Interpro	IPR009240 APC_15aa [ SRS ]    IPR009240 APC_15aa [ EBI ]
Interpro	IPR009234 APC_basic [ SRS ]    IPR009234 APC_basic [ EBI ]
Interpro	IPR009223 APC_crr [ SRS ]    IPR009223 APC_crr [ EBI ]
Interpro	IPR011989 ARM-like [ SRS ]    IPR011989 ARM-like [ EBI ]
Interpro	IPR000225 Armadillo [ SRS ]    IPR000225 Armadillo [ EBI ]
Interpro	IPR009232 EB1_bd [ SRS ]    IPR009232 EB1_bd [ EBI ]
Interpro	IPR009224 SAMP [ SRS ]    IPR009224 SAMP [ EBI ]
CluSTr	P25054
Pfam	PF05972 APC_15aa [ SRS ]    PF05972 APC_15aa [ Sanger ]    pfam05972 [ NCBI-CDD ]
Pfam	PF05956 APC_basic [ SRS ]    PF05956 APC_basic [ Sanger ]    pfam05956 [ NCBI-CDD ]
Pfam	PF05923 APC_crr [ SRS ]    PF05923 APC_crr [ Sanger ]    pfam05923 [ NCBI-CDD ]
Pfam	PF00514 Arm [ SRS ]    PF00514 Arm [ Sanger ]    pfam00514 [ NCBI-CDD ]
Pfam	PF05937 EB1_binding [ SRS ]    PF05937 EB1_binding [ Sanger ]    pfam05937 [ NCBI-CDD ]
Pfam	PF05924 SAMP [ SRS ]    PF05924 SAMP [ Sanger ]    pfam05924 [ NCBI-CDD ]
Smart	SM00185 ARM [EMBL]
Blocks	P25054
PDB	1DEB [ SRS ]    1DEB [ PdbSum ],   1DEB [ IMB ]   1DEB [ RSDB ]
PDB	1EMU [ SRS ]    1EMU [ PdbSum ],   1EMU [ IMB ]   1EMU [ RSDB ]
PDB	1JPP [ SRS ]    1JPP [ PdbSum ],   1JPP [ IMB ]   1JPP [ RSDB ]
PDB	1M5I [ SRS ]    1M5I [ PdbSum ],   1M5I [ IMB ]   1M5I [ RSDB ]
PDB	1T08 [ SRS ]    1T08 [ PdbSum ],   1T08 [ IMB ]   1T08 [ RSDB ]
PDB	1TH1 [ SRS ]    1TH1 [ PdbSum ],   1TH1 [ IMB ]   1TH1 [ RSDB ]
PDB	1V18 [ SRS ]    1V18 [ PdbSum ],   1V18 [ IMB ]   1V18 [ RSDB ]
HPRD	01439
	Protein Interaction databases
DIP	P25054
IntAct	P25054
	Polymorphism : SNP, mutations, diseases
OMIM	135290;137215;155255;175100;276300    [ map ]
GENECLINICS	135290;137215;155255;175100;276300
SNP	APC [dbSNP-NCBI]
SNP	NM_000038 [SNP-NCI]
SNP	APC [GeneSNPs - Utah]  APC] [HGBASE - SRS]
HAPMAP	APC [HAPMAP]
COSMIC	APC [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	APC
	General knowledge
Family Browser	APC [UCSC Family Browser]
SOURCE	NM_000038
SMD	Hs.158932
SAGE	Hs.158932
GO	kinetochore [Amigo]  kinetochore
GO	nucleus [Amigo]  nucleus
GO	cytoplasm [Amigo]  cytoplasm
GO	centrosome [Amigo]  centrosome
GO	protein complex assembly [Amigo]  protein complex assembly
GO	response to DNA damage stimulus [Amigo]  response to DNA damage stimulus
GO	negative regulation of microtubule depolymerization [Amigo]  negative regulation of microtubule depolymerization
GO	cell cycle [Amigo]  cell cycle
GO	cell cycle arrest [Amigo]  cell cycle arrest
GO	cell adhesion [Amigo]  cell adhesion
GO	beta-catenin binding [Amigo]  beta-catenin binding
GO	beta-catenin binding [Amigo]  beta-catenin binding
GO	microtubule binding [Amigo]  microtubule binding
GO	negative regulation of cell proliferation [Amigo]  negative regulation of cell proliferation
GO	protein kinase CK2 regulator activity [Amigo]  protein kinase CK2 regulator activity
GO	lateral plasma membrane [Amigo]  lateral plasma membrane
GO	protein kinase binding [Amigo]  protein kinase binding
GO	beta-catenin destruction complex [Amigo]  beta-catenin destruction complex
GO	negative regulation of cyclin-dependent protein kinase activity [Amigo]  negative regulation of cyclin-dependent protein kinase activity
GO	regulation of attachment of spindle microtubules to kinetochore [Amigo]  regulation of attachment of spindle microtubules to kinetochore
GO	Wnt receptor signaling pathway through beta-catenin [Amigo]  Wnt receptor signaling pathway through beta-catenin
GO	Wnt receptor signaling pathway through beta-catenin [Amigo]  Wnt receptor signaling pathway through beta-catenin
BIOCARTA	ALK in cardiac myocytes    [Genes]
BIOCARTA	Inactivation of Gsk3 by AKT causes accumulation of b-catenin in Alveolar Macrophages    [Genes]
BIOCARTA	Multi-step Regulation of Transcription by Pitx2    [Genes]
BIOCARTA	Presenilin action in Notch and Wnt signaling    [Genes]
BIOCARTA	TGF beta signaling pathway    [Genes]
BIOCARTA	WNT Signaling Pathway    [Genes]
KEGG	Wnt signaling pathway
KEGG	Regulation of actin cytoskeleton
KEGG	Colorectal cancer
PubGene	APC
TreeFam	APC
CTD	324 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	Cancer Cytogenetics (Bari)
Probe	APC Related clones (RZPD - Berlin)
	PubMed
PubMed	243 Pubmed reference(s) in LocusLink

Bibliography

Identification and characterization of the familial adenomatous polyposis coli gene.

Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, Joslyn G, Stevens J, Spirio L, Robertson M

Cell. 1991 ; 66 (3) : 589-600.

PMID 1651174

Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients.

Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, Koyama K, Utsunomiya J, Baba S, Hedge P

Science (New York, N.Y.). 1991 ; 253 (5020) : 665-669.

PMID 1651563

APC mutations occur early during colorectal tumorigenesis.

Powell SM, Zilz N, Beazer-Barclay Y, Bryan TM, Hamilton SR, Thibodeau SN, Vogelstein B, Kinzler KW

Nature. 1992 ; 359 (6392) : 235-237.

PMID 1528264

Lessons from hereditary colorectal cancer.

Kinzler KW, Vogelstein B

Cell. 1996 ; 87 (2) : 159-170.

PMID 8861899

Biology of the adenomatous polyposis coli tumor suppressor.

Goss KH, Groden J

Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2000 ; 18 (9) : 1967-1979.

PMID 10784639

The adenomatous polyposis coli protein: the Achilles heel of the gut epithelium.

Nˆ§thke IS

Annual review of cell and developmental biology. 2004 ; 20 : 337-366.

PMID 15473844

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

Search in all EBI   NCBI

Contributor(s)

Written	04-1998	Richard Hamelin
		INSERM U434, CEPH, 27, rue Juliette Dodu, 75010 Paris, France

Citation

This paper should be referenced as such :

Hamelin P . APC (adenomatous polyposis coli). Atlas Genet Cytogenet Oncol Haematol. April 1998 . URL : http://AtlasGeneticsOncology.org/Genes/APC118.html

Tirnauer J . APC (adenomatous polyposis coli). Atlas Genet Cytogenet Oncol Haematol. . URL : http://AtlasGeneticsOncology.org/Genes/APC118.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Wed Jul 2 08:21:52 2008