ABCC1
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Location (UCSC) | Chr 16: 15.95 – 16.14 Mb | Chr 16: 14.18 – 14.29 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Multidrug resistance-associated protein 1 (MRP1) is a protein that in humans is encoded by the ABCC1 gene.[5][6]
Function
The protein encoded by this gene is a member of the superfamily of
Structure
ABCC1 is a 190 kDa protein that contains two membrane-spanning domains of hydrophobic nature and two nucleotide binding domains.[8] 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.[8] 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.[9] ABCC1 is a highly conserved gene with
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.[10] 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.[10]
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.[10] 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.[10] 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.[10]
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.[11]
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.[12] 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.[12] In prostate cancer, expression of ABCC1 was found to increase with the stage of the disease while allowing resistance to chemotherapeutic drugs.[12]
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
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ^ The interactive pathway map can be edited at WikiPathways: "IrinotecanPathway_WP229".
See also
- ATP-binding cassette transporter
- P-glycoprotein (Multidrug resistance protein- MDR1). Not to be confused with Multidrug resistance-associated protein (MRP1)
References
- ^ a b c ENSG00000103222 GRCh38: Ensembl release 89: ENSG00000278183, ENSG00000103222 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000023088 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 8098549.
- PMID 1360704.
- ^ "Entrez Gene: ABCC1 ATP-binding cassette, sub-family C (CFTR/MRP), member 1".
- ^ PMID 11279022.
- PMID 25281745.
- ^ PMID 22086004.
- PMID 24746857.
- ^ S2CID 33902808.
- PMID 21881209.
- PMID 24156265.
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. 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. 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. 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. 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. 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.