ABCC1

ABCC1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2CBZ, 4C3Z
Identifiers
Aliases	ABCC1, ABC29, ABCC, GS-X, MRP, MRP1, ATP binding cassette subfamily C member 1, DFNA77
External IDs	OMIM: 158343; MGI: 102676; HomoloGene: 133779; GeneCards: ABCC1; OMA:ABCC1 - orthologs
Gene location (Human) Chr. Chromosome 16 (human) Band 16p13.11 Start 15,949,138 bp End 16,143,257 bp
Gene location (Mouse) Chr. Chromosome 16 (mouse) Band 16|16 A1 Start 14,179,422 bp End 14,293,601 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in stromal cell of endometrium ascending aorta gastric mucosa left lobe of thyroid gland right lobe of thyroid gland Descending thoracic aorta prostate bone marrow cells skeletal muscle tissue spleen Top expressed in stroma of bone marrow skin of external ear endothelial cell of lymphatic vessel olfactory epithelium conjunctival fornix ankle ascending aorta retinal pigment epithelium tunica media of zone of aorta hair follicle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function ATPase-coupled transmembrane transporter activity nucleotide binding ATPase activity hydrolase activity ATP binding transporter activity ATPase-coupled inorganic anion transmembrane transporter activity ABC-type vitamin B12 transporter activity ABC-type xenobiotic transporter activity ABC-type glutathione S-conjugate transporter activity glutathione transmembrane transporter activity ATPase-coupled intramembrane lipid transporter activity sphingolipid floppase activity transmembrane transporter activity Cellular component integral component of membrane plasma membrane basolateral plasma membrane membrane extracellular exosome integral component of plasma membrane vacuolar membrane Biological process cobalamin metabolic process leukotriene metabolic process transmembrane transport cobalamin transport vitamin transmembrane transport xenobiotic transmembrane transport glutathione transmembrane transport xenobiotic transport transport phospholipid translocation cell chemotaxis sphingolipid translocation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4363 17250 Ensembl ENSG00000278183 ENSG00000103222 ENSMUSG00000023088 UniProt P33527 O35379 RefSeq (mRNA) NM_004996 NM_019862 NM_019898 NM_019899 NM_019900 NM_019901 NM_019902 NM_008576 RefSeq (protein) NP_004987 NP_032602 Location (UCSC) Chr 16: 15.95 – 16.14 Mb Chr 16: 14.18 – 14.29 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Multidrug resistance-associated protein 1 (MRP1) is a protein that in humans is encoded by the ABCC1 gene.

Function

The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra-and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This full transporter is a member of the MRP subfamily which is involved in multi-drug resistance. This protein functions as a multispecific organic anion transporter, with oxidized glutathione, cysteinyl leukotrienes, and activated aflatoxin B1 as substrates. This protein also transports glucuronides and sulfate conjugates of steroid hormones and bile salts. Alternative splicing by exon deletion results in several splice variants but maintains the original open reading frame in all forms.

Structure

ABCC1 is a 190 kDa protein that contains two membrane-spanning domains of hydrophobic nature and two nucleotide binding domains. Each membrane-spanning domain is made up of six α-helices. In addition, the protein also contains a third membrane-spanning domain that sets it apart from other transporters within the ATP-binding cassette family of transporters. The two nucleotide binding domains have a functional asymmetry that plays a significant role in the ability of ATP to power the transporter. The first nucleotide binding domain, which is delegated NBD1, is responsible for the strong attraction of ATP to the transporter. The second nucleotide binding domain, NBD2, is the domain responsible for the hydrolysis of ATP. This asymmetry is specific to the C subfamily of ABC transporters and is generally not found in other transporters. ABCC1 is a highly conserved gene with polymorphisms occurring at very low frequencies of less than five percent. Polymorphisms in this gene are generally found in the form of a single-nucleotide polymorphism (SNP). The greatest ethnic differences in polymorphisms within the ABCC1 are found between Caucasian and Asian populations. There are multiple examples of single nucleotide polymorphisms that are shared among Asian populations but not found in Caucasian populations and vice versa.

Genomic location and tissue expression

The ABCC1 gene, the gene that encodes the ABCC1 protein, is found on chromosome 16 within the nucleus. The protein resides intracellularly on the basolateral side of the plasma membrane which differs from other ATP-binding cassette transporters that are found on the apical side of the membrane. While ABCC1 is generally found throughout most tissues in humans, it is particularly prevalent in the lungs, spleen, testes, kidneys, placenta, thyroid, bladder, and adrenal glands. It is also found in the endothelium cells of the blood-brain barrier.

Clinical significance

Effect of polymorphisms

Certain polymorphisms in the ABCC1 gene have been shown to be connected with an increased susceptibility to certain types of cancer. A G2168A polymorphism and polymorphisms found in the 3'-UTR region of the gene have been shown to have a connection with increased susceptibility to lung cancer, especially in Chinese populations. Carriers of the G2168A polymorphism contract lung cancer at a rate nearly four times higher than those individuals that do not have the mutation in the gene. Polymorphisms within the ABCC1 gene also tend to have a substantial effect on the severity of a disease. Examples of these diseases includes cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). In reference to cystic fibrosis, individuals with a G-260C polymorphism in the 5'-UTR area of the ABCC1 gene tended to have a much more severe case of cystic fibrosis than individuals with the wild-type gene. Individuals with chronic obstructive pulmonary disorder were impacted by two polymorphisms in the ABCC1 gene. If an individual had a 3'-UTR T866A polymorphism, they generally had a less severe case of COPD marked by less inflammation in their airways. On the other hand, an individual with a 3'-UTR G3361A polymorphism generally had a more severe case of COPD that was accompanied by a greater amount of inflammation in their airways.

Alzheimer's disease

The ATP-binding cassette protein ABCC1 has received attention in the last decade due to its possible connection with Alzheimer's disease. One of the more prominent signs of Alzheimer's disease is the accumulation of β-amyloid proteins in the brain. As these proteins accumulate, they begin to form plaques that interfere with signaling between cells of the nervous system found within the brain. Due to its presence in the choroid plexus and blood-brain barrier and its ability to transport multiple kinds of molecules out of cells, ABCC1 has been a point of interest in many Alzheimer's disease studies. The transporter protein has been shown to decrease β-amyloid accumulation by nearly 80 percent when activated, leading researchers to further investigation on its use in future treatments of Alzheimer's and other neurological disorders.

Role in cancer

ABCC1 plays a role in the multidrug resistance of cancerous tumor cells due to its ability to transport many chemotherapeutic drugs out of the cells. The ABCC1 transporter protein is especially prevalent in neuroblastoma and cancer cells found in the lung, breast and prostate. In non-small cell lung carcinoma and small cell lung carcinoma, higher expression of ABCC1 was indicative of a reduced response to chemotherapeutic drugs and a lower rate of survival. Similar results were found in early-stage breast cancer where the increased expression of the transporter gene correlated with shorter times until a relapse occurred and lower rates of survival. In prostate cancer, expression of ABCC1 was found to increase with the stage of the disease while allowing resistance to chemotherapeutic drugs.

Animal studies

Because of its significant role in the transportation of organic anion molecules and recent association with multiple illnesses including Alzheimer's disease (AD), the ABCC1 protein has become a potential drug target. In ABBC1 knockout mice, β-amyloid clearance is much lower than in wild-type mice that expressed the gene. Furthermore, in mouse models of AD, treatment with thiethylperazine, a drug that activates ABBC1, increases β-amyloid clearance and decreases in the amount of β-amyloid found in the brains.

St. John's wort, a substance containing the chemical hyperforin, has also been shown to have a positive effect on activity levels of ABCC1. In a study of the effects of St. John's wort on APP-tg mice, an extract of St. John's wort that contained decreased levels of hyperforin increased the activity of ABCC1 by 70 percent and led to decreased amounts of β-amyloid in the brain and increased cognitive function in the mice.

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.

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Irinotecan Pathway edit

See also

• ATP-binding cassette transporter
• P-glycoprotein (Multidrug resistance protein- MDR1). Not to be confused with Multidrug resistance-associated protein (MRP1)

Further reading

• Lautier D, Canitrot Y, Deeley RG, Cole SP (October 1996). "Multidrug resistance mediated by the multidrug resistance protein (MRP) gene". Biochemical Pharmacology. 52 (7): 967–77. doi:10.1016/0006-2952(96)00450-9. PMID 8831715.
• Deeley RG, Cole SP (June 1997). "Function, evolution and structure of multidrug resistance protein (MRP)". Seminars in Cancer Biology. 8 (3): 193–204. doi:10.1006/scbi.1997.0070. PMID 9441948.
• Hegedus T, Orfi L, Seprodi A, Váradi A, Sarkadi B, Kéri G (July 2002). "Interaction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and MRP1". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1587 (2–3): 318–25. doi:10.1016/s0925-4439(02)00095-9. PMID 12084474.
• Chang XB (March 2007). "A molecular understanding of ATP-dependent solute transport by multidrug resistance-associated protein MRP1". Cancer and Metastasis Reviews. 26 (1): 15–37. doi:10.1007/s10555-007-9041-7. PMID 17295059. S2CID 20660134.
• Wijnholds J, deLange EC, Scheffer GL, van den Berg DJ, Mol CA, van der Valk M, Schinkel AH, Scheper RJ, Breimer DD, Borst P (February 2000). "Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier" (PDF). The Journal of Clinical Investigation. 105 (3): 279–85. doi:10.1172/JCI8267. PMC 377447. PMID 10675353.

External links

• ABCC1+protein,+ human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human ABCC1 genome location and ABCC1 gene details page in the UCSC Genome Browser.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.