Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P33527 (ABCC1)
 1,164 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multidrug resistance (MDR) in cancer cells is a major contributor to the failure of chemotherapy treatment. This paper describes a novel protein named the anthracycline resistance associated (ARA) protein. The ara gene is amplified in the MDR leukaemia line CCRF-CEM/E1000 and its mRNA is overexpressed. ARA belongs to the ATP binding cassette (ABC) family of proteins. Another ABC protein, the multidrug resistance-associated protein (MRP), has previously been reported to be overexpressed in the CEM/E1000 subline. The primary amino acid sequence of ARA indicates that it is 49.5 kDa without glycosylation, and that it has one potential glycosylation site. ARA has one ATP binding site and associated transmembrane regions. This is in contrast to MRP (190 kDa, 172 kDa deglycosylated) and most other higher eukaryote ABC proteins, which consist of two similar halves, each having one ATP binding site. In addition to ARA being coexpressed with MRP, comparison of amino acid sequences showed that, among known proteins, ARA is most similar to the C-terminal half of MRP.
 ...
PMID:The anthracycline resistance-associated (ara) gene, a novel gene associated with multidrug resistance in a human leukaemia cell line. 891 25

Pseudoxanthoma elasticum (PXE) is a mendelian disorder characterized by calcification of elastic fibers in skin, arteries, and retina. It results in dermal lesions, arterial insufficiency and retinal hemorrhages, leading to macular degeneration. PXE is transmitted either as an autosomal dominant or recessive trait and several sporadic cases have been observed. Mutations in the ABCC6 gene have been identified very recently in patients. Here, we report on a large Italian family affected by pseudoxanthoma elasticum for which linkage analysis had pointed to a region encompassing markers D16S3069-D16S405-D16S3103; hemizygosity of marker D16S405 allowed us to detect a submicroscopic deletion of at least 900 kb involving ABCC6, ABCC1, and MYH11. Mutation analysis on the other allele of the family, as well as on two additional sporadic cases, revealed nonsense (Y227X, R518X, R1164X) and frame-shift (c.960delC) mutations in ABCC6 (MRP6) further confirming the role of this multi-drug resistance gene in the etiology of pseudoxanthoma elasticum. Furthermore, clinical re-examination of members of the family harboring the deletion led to the detection of additional features, potentially caused by the deletion of the MYH11 gene. In the course of the analysis five nonpathogenic variants were found in ABCC6: 1233T>C, 1245G>A, 1838 T>G (V614A), 1890C>G, and 3506+83C>A. Hum Mutat 18:85, 2001.
 ...
PMID:Pseudoxanthoma elasticum: Point mutations in the ABCC6 gene and a large deletion including also ABCC1 and MYH11. 1143 1

Several years ago, we initiated a long-term project of cloning new human ATP-binding cassette (ABC) transporters and linking them to various disease phenotypes. As one of the results of this project, we present two new members of the human ABCC subfamily, ABCC11 and ABCC12. These two new human ABC transporters were fully characterized and mapped to the human chromosome 16q12. With the addition of these two genes, the complete human ABCC subfamily has 12 identified members (ABCC1-12), nine from the multidrug resistance-like subgroup, two from the sulfonylurea receptor subgroup, and the CFTR gene. Phylogenetic analysis determined that ABCC11 and ABCC12 are derived by duplication, and are most closely related to the ABCC5 gene. Genetic variation in some ABCC subfamily members is associated with human inherited diseases, including cystic fibrosis (CFTR/ABCC7), Dubin-Johnson syndrome (ABCC2), pseudoxanthoma elasticum (ABCC6) and familial persistent hyperinsulinemic hypoglycemia of infancy (ABCC8). Since ABCC11 and ABCC12 were mapped to a region harboring gene(s) for paroxysmal kinesigenic choreoathetosis, the two genes represent positional candidates for this disorder.
 ...
PMID:Two new genes from the human ATP-binding cassette transporter superfamily, ABCC11 and ABCC12, tandemly duplicated on chromosome 16q12. 1148 64

Mutations in the ABCC6 (MRP6) gene cause pseudoxanthoma elasticum (PXE), a rare heritable disorder resulting in the calcification of elastic fibers. In the present study a cDNA encoding a full-length normal variant of ABCC6 was amplified from a human kidney cDNA library, and the protein was expressed in Sf9 insect cells. In isolated membranes ATP binding as well as ATP-dependent active transport by ABCC6 was demonstrated. We found that glutathione conjugates, including leukotriene C(4) and N-ethylmaleimide S-glutathione (NEM-GS), were actively transported by human ABCC6. Organic anions (probenecid, benzbromarone, indomethacin), known to interfere with glutathione conjugate transport of human ABCC1 and ABCC2, inhibited the ABCC6-mediated NEM-GS transport in a specific manner, indicating that ABCC6 has a unique substrate specificity. We have also expressed three missense mutant forms of ABCC6, which have recently been shown to cause PXE. MgATP binding was normal in these proteins; ATP-dependent NEM-GS or leukotriene C(4) transport, however, was abolished. Our data indicate that human ABCC6 is a primary active transporter for organic anions. In the three ABCC6 mutant forms examined, the loss of transport activity suggests that these mutations result in a PXE phenotype through a direct influence on the transport activity of this ABC transporter.
 ...
PMID:Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6). 1188 Mar 68

The ABCC6 gene encodes MRP6, a member of the multidrug resistance-associated protein (MRP) family. Interest in ABCC6/MRP6 derives, in part, from the fact that mutations in this gene/protein system have been identified in families with pseudoxanthoma elasticum (PXE). Early studies indicated that ABCC6 is expressed primarily in the liver and to a lesser extent in the kidney, but more recently a widespread distribution has been suggested. To explore the tissue-specific expression of ABCC6, we first examined various mouse tissues by RT-PCR. The results indicated high levels of mRNA in the liver, whereas low level of expression was noted in the kidney and small intestine. To explore other tissues in which initial RT-PCR was essentially negative, a second-round nested PCR was performed, which revealed expression also in the brain, tongue, stomach, and eye. Unexpectedly, however, distinct PCR products of smaller molecular weight were noted in these tissues. Subcloning and sequencing of these PCR products indicated that they reflected aberrant splicing in the 3' end of the ABCC6 mRNA, resulting in each case in a premature termination codon. Similar results were noted with RT-PCR analysis using RNA isolated from cultured human epidermal keratinocytes and dermal fibroblasts. Collectively, our results confirm high level of expression of ABCC6 in the liver and the kidney, whereas very low level of expression in a variety of other tissues was noted. The results have implications for mutation detection strategies in PXE by RT-PCR, and they further support the notion that PXE is a primary metabolic disorder.
 ...
PMID:Tissue-specific expression of the ABCC6 gene. 1629 87

The gene encoding the ABCC6 protein, an ABC transporter of the multidrug resistance-associated protein (MRP), is mainly expressed in liver and kidney. Mutations in ABCC6 are responsible for the development of the pseudoxanthoma elasticum (PXE) phenotype. PXE is a recessive disease characterized by the calcification of elastic fibers resulting in dermal, vascular, and ocular clinical manifestations. The physiological function of ABCC6 and the rodent orthologs Abcc6 is unknown and their precise relationship to elastic fibers is only a matter of speculation. Despite several studies focused on the transcriptional regulation of ABCC6/Abcc6, the molecular signals conferring the tissue-specificity to the ABCC6/Abcc6 expression are not well defined. In this report, we determined the level of the mouse Abcc6 promoter methylation in tissues with low level of expression (tail extremity and skin), intermediate (kidney), and high level of expression (liver). We observed that high and moderate levels of methylation correlated with low levels of Abcc6 expression. Moreover, we determined that CpG methylation of the Abcc6 proximal promoter region was interfering with the binding of the Sp1 transcription factor thereby inhibiting Sp1-dependent transactivation. Thus, our data provide the first direct evidence that an epigenetic mechanism regulates the binding of transcription factor Sp1 to the proximal promoter and participates in the tissue-specific expression control of the mouse Abcc6 gene.
 ...
PMID:DNA methylation and Sp1 binding determine the tissue-specific transcriptional activity of the mouse Abcc6 promoter. 1721 63

1. The multidrug resistance-associated proteins (MRPs) belong to the ATP-binding cassette superfamily (ABCC family) of transporters that are expressed differentially in the liver, kidney, intestine and blood-brain barrier. There are nine human MRPs that transport a structurally diverse array of endo- and xenobiotics as well as their conjugates. 2. Multidrug resistance-associated protein 1 can be distinguished from MRP2 and MRP3 by its higher affinity for leukotriene C(4). Unlike MRP1, MRP2 functions in the extrusion of endogenous organic anions, such as bilirubin glucuronide and certain anticancer agents. In addition to the transport of glutathione and glucuronate conjugates, MRP3 has the additional capability of mediating the transport of monoanionic bile acids. 3. Both MRP4 and MRP5 are able to mediate the transport of cyclic nucleotides and confer resistance to certain antiviral and anticancer nucleotide analogues. Hereditary deficiency of MRP6 results in pseudoxanthoma elasticum. In the body, MRP6 is involved in the transport of glutathione conjugates and the cyclic pentapeptide BQ123. 4. Various MRPs show considerable differences in tissue distribution, substrate specificity and proposed physiological function. These proteins play a role in drug disposition and excretion and thus are implicated in drug toxicity and drug interactions. Increased efflux of natural product anticancer drugs and other anticancer agents mediated by MRPs from cancer cells is associated with tumour resistance. 5. A better understanding of the function and regulating mechanisms of MRPs could help minimize and avoid drug toxicity and unfavourable drug-drug interactions, as well as help overcome drug resistance.
 ...
PMID:Multidrug resistance-associated proteins and implications in drug development. 1956 19

Vitamin K is a cofactor required for gamma-glutamyl carboxylation of several proteins regulating blood clotting, bone formation and soft tissue mineralization. Vitamin K3 is an important intermediate during conversion of the dietary vitamin K1 to the most abundant vitamin K2 form. It has been suggested that ABCC6 may have a role in transporting vitamin K or its derivatives from the liver to the periphery. This activity is missing in pseudoxanthoma elasticum, a genetic disorder caused by mutations in ABCC6 characterized by abnormal soft tissue mineralization. Here we examined the efflux of the glutathione conjugate of vitamin K3 (VK3GS) from the liver in wild type and Abcc6(-/-) mice, and in transport assays in vitro. We found in liver perfusion experiments that VK3GS is secreted into the inferior vena cava, but we observed no significant difference between wild type and Abcc6(-/-) animals. We overexpressed the human ABCC6 transporter in Sf9 insect and MDCKII cells and assayed its vitamin K3-conjugate transport activity in vitro. We found no measurable transport of VK3GS by ABCC6, whereas ABCC1 transported this compound at high rate in these assays. These results show that VK3GS is not the essential metabolite transported by ABCC6 from the liver and preventing the symptoms of pseudoxanthoma elasticum.
 ...
PMID:ABCC6 does not transport vitamin K3-glutathione conjugate from the liver: relevance to pathomechanisms of pseudoxanthoma elasticum. 2205 57