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)

Tumor cells may become resistant to conventional anticancer drugs through the occurrence of transmembrane transporter proteins such as P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), or members of the multidrug resistance-associated protein family (MRP1-MRP5; ABCC1-ABCC5). In this report, we studied whether tumor cells that are cytostatic drug resistant because of overexpression of one of the above mentioned proteins are sensitive to a new anticancer agent, interleukin-4 toxin (IL-4 toxin). IL-4 toxin is a fusion protein composed of circularly permuted IL-4 and a truncated form of Pseudomonas exotoxin (PE) [IL-4(38-37)-PE38KDEL]. Ninety-six-h cytotoxicity assays and 10-day clonogenic assays showed that drug-selected multidrug resistant (MDR) tumor cells that overexpress P-glycoprotein or breast cancer resistance proteins are still sensitive to IL-4 toxin. Also, tumor cells transfected with cDNA for MRP2-5 showed no resistance, or marginal resistance, only to the toxin as compared with the parent cells. In contrast, MRP1-overexpressing cells, both drug selected and MRP1 transfected, are clearly resistant to IL-4 toxin with resistance factors of 4.3 to 8.4. MRP1-overexpressing cells were not resistant to PE itself. IL-4 toxin resistance in MRP1-overexpressing cells could be reversed by the MRP1 inhibitors probenecid or MK571 and were not affected by glutathione depletion by DL-buthionine-S,R-sulfoximine. In a transport assay using plasma membrane vesicles prepared from MRP1-overexpressing cells, IL-4 toxin and IL-4, but not PE, inhibited the translocation of the known MRP1 substrate 17beta-estradiol 17-(beta-D-glucuronide) (E(2)17betaG). These data suggest that MRP1-overexpressing cells are resistant to IL-4 toxin because of extrusion of this agent by MRP1. Still, the results of this study demonstrate that IL-4 toxin effectively kills most MDR tumor cells and, therefore, represents a promising anticancer drug.
 ...
PMID:Multidrug-resistant tumor cells remain sensitive to a recombinant interleukin-4-Pseudomonas exotoxin, except when overexpressing the multidrug resistance protein MRP1. 1458 76

The multidrug resistance protein 1 (MRP1/ABCC1) is an ATP-driven transporter that mediates the cellular extrusion of various chemotherapeutic agents. We have previously isolated a novel recombinant single-chain Fv antibody (A5scFv), which specifically targets the extracellular N-terminus of the human MRP1 expressed on the surface of live tumor cells. Fusion of A5scFv to Pseudomonas exotoxin revealed an immunotoxin that bound to the immobilized MRP1-derived peptide upon ELISA, but surprisingly failed to recognize MRP1 on the surface of live tumor cells. As these results suggested that the N-terminus of MRP1 has a limited accessibility to the extracellular space, we used the A5scFv antibody to probe for putative conformational changes that might occur in viable tumor cells upon ATP binding. A5scFv recognized viable MRP1-expressing cells with intact ATP pools, whereas ATP depletion resulted in the loss of A5scFv reactivity. Consistently, restoration of cellular ATP levels resulted in resumption of A5scFv binding to MRP1 in live tumor cells. Flow cytometric analysis confirmed that ATP-depleted cells accumulated significantly higher levels of the established substrate calcein AM, whereas after restoration of cellular ATP pools, cells displayed a much lower level of calcein AM accumulation. Moreover, pretreatment of MRP1-expressing cells with the membrane fluidizer benzyl alcohol resulted in a dramatic increase in A5scFv reactivity, suggesting that membrane fluidization results in the exposure of the N-terminus of MRP1 to the extracellular milieu. These results constitute the first extracellular probing of the putative conformational changes that MRP1 adopts in viable tumor cells upon ATP binding. Furthermore, although ATP binding occurs in the cytosolic nucleotide binding domains of MRP1, significant conformational changes are apparently propagated to the N-terminus residing at the extracellular compartment.
 ...
PMID:Probing ATP-dependent conformational changes in the multidrug resistance protein 1 (MRP1/ABCC1) in live tumor cells with a novel recombinant single-chain Fv antibody targeted to the extracellular N-terminus. 1583 32

The ABCC1 gene is structurally and functionally related to the cystic fibrosis transmembrane conductance regulator gene (CFTR). Upregulation of ABCC1 is thought to improve lung function in patients with cystic fibrosis (CF); the mechanism underlying this effect is unknown. We analyzed the ABCC1 promoter single nucleotide polymorphism (SNP rs504348), plasma-induced ABCC1 mRNA expression levels, and ABCC1 methylation status and their correlation with clinical variables among CF subjects with differing CFTR mutations. We assigned 93 CF subjects into disease severity groups and genotyped SNP rs504348. For 23 CF subjects and 7 healthy controls, donor peripheral blood mononuclear cells (PBMCs) stimulated with plasma underwent gene expression analysis via qRT-PCR. ABCC1 promoter methylation was analyzed in the same 23 CF subjects. No significant correlation was observed between rs504348 genotypes and CF disease severity, but pancreatic insufficient CF subjects showed increased colonization with any form of Pseudomonas aeruginosa (OR = 3.125, 95% CI: 1.192-8.190) and mucoid P. aeruginosa (OR = 5.075, 95% CI: 1.307-28.620) compared to the pancreatic sufficient group. A significantly higher expression of ABCC1 mRNA was induced by CF plasma compared to healthy control plasma (p < 0.001). CF subjects with rs504348 (CC/CG) also had higher mRNA expression compared to those with the ancestral GG genotype (p < 0.005). ABCC1 promoter was completely unmethylated; therefore, we did not detect any association between methylation and CF disease severity. In silico predictions suggested that histone modifications are crucial for regulating ABCC1 expression in PBMCs. Our results suggest that ABCC1 expression has a role in CFTR activity thereby increasing our understanding of the molecular underpinnings of the clinical heterogeneity in CF.
 ...
PMID:Increased Expression of Plasma-Induced ABCC1 mRNA in Cystic Fibrosis. 2880 Jan 22