Affinage

ABCC4

ATP-binding cassette sub-family C member 4 · UniProt O15439

Length
1325 aa
Mass
149.5 kDa
Annotated
2026-06-09
100 papers in source corpus 47 papers cited in narrative 47 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ABCC4/MRP4 is an ATP-binding cassette transporter that couples substrate-stimulated ATP hydrolysis to the efflux of a broad range of organic anions, governing both xenobiotic disposition and intracellular cyclic-nucleotide signaling across many cell types (PMID:9661885, PMID:11856762, PMID:15364914). Biochemically it hydrolyzes ATP in a substrate-stimulated manner with ADP release as the likely rate-limiting step, and transmembrane helix-6 residues (Arg375, Phe368) form a substrate-discriminating binding pocket that handles methotrexate, E2-17β-glucuronide, and cyclic nucleotides differentially (PMID:15364914, PMID:18612080, PMID:22542979). Its substrate range spans cyclic nucleotides cAMP/cGMP, prostaglandins and thromboxane, leukotrienes (LTB4 GSH-dependent, LTC4 GSH-independent), bile acids co-transported with glutathione, folates/methotrexate, urate, p-aminohippurate, sulfate conjugates, sphingosine-1-phosphate, methylated arsenicals, and numerous nucleoside/nucleotide analog drugs (PMID:11856762, PMID:12835412, PMID:12036927, PMID:15454390, PMID:16282361, PMID:17959747, PMID:15504935, PMID:24870404, PMID:29304533). Through this transport activity MRP4 confers resistance to antiviral and antineoplastic agents (PMEA, AZT, ganciclovir, adefovir/tenofovir, cytarabine) and, at apical membranes of kidney proximal tubule, choroid plexus and brain capillaries, restricts renal accumulation and CNS penetration of drugs—cooperating with ABCB1 and ABCG2 to form a redundant blood-brain barrier efflux system (PMID:10470083, PMID:15314169, PMID:12105214, PMID:17110501, PMID:26842729, PMID:23461902). By extruding cAMP and cGMP, MRP4 sets intracellular cyclic-nucleotide tone to control platelet activation and thrombus formation, vascular smooth-muscle tone in pulmonary hypertension, cardiomyocyte contractility, cell migration, and leukemic differentiation, in several settings acting through CFTR/PDZK1-scaffolded microdomains (PMID:21205825, PMID:21670499, PMID:25762723, PMID:23264633, PMID:22381067, PMID:26405223, PMID:26316625). In the liver it mediates basolateral extrusion of bile acids and sulfate conjugates and is protective in obstructive cholestasis (PMID:16628672, PMID:16988054). A transport-independent function additionally allows MRP4 to bind and stabilize β-catenin, sustaining Wnt signaling and embryo implantation in endometrium (PMID:31410201). Expression is transcriptionally controlled by CAR, AhR and Nrf2, post-transcriptionally by miR-124a/miR-506 and nonsense-mediated decay, and surface levels are set by SNX27-mediated endocytosis (PMID:15004017, PMID:20395535, PMID:22411990, PMID:24184504, PMID:12499391).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 High

    Establishing the molecular identity of ABCC4 as a distinct MRP-family ABC transporter answered whether this gene encoded a transporter and defined its structural distinction (lacking the N-terminal hydrophobic extension) from MRP1/cMOAT.

    Evidence Degenerate PCR cloning, FISH mapping to 13q32, and Northern tissue profiling

    PMID:9661885

    Open questions at the time
    • No transport substrate or function defined at cloning
    • Subcellular localization not addressed
  2. 1999 High

    Linking MRP4 overexpression to ATP-dependent efflux of nucleotide analogs established its first functional role as a drug-resistance efflux pump.

    Evidence Drug-selected/amplified cell lines, chromosome transfer, and ATP-dependent efflux assays

    PMID:10470083

    Open questions at the time
    • Endogenous physiological substrates not yet known
    • Mechanism of ATP coupling uncharacterized
  3. 2002 High

    Demonstrating direct ATP-dependent transport of cAMP and cGMP in reconstituted vesicles, plus apical kidney localization, redefined MRP4 as a cyclic-nucleotide and organic-anion efflux pump with a renal excretory role.

    Evidence Inside-out Sf9 vesicle transport with saturation kinetics and human kidney immunolocalization

    PMID:11856762

    Open questions at the time
    • Physiological consequence of cyclic-nucleotide efflux not yet tested in vivo
    • Single-substrate kinetics did not address polyspecificity
  4. 2003 Medium

    Identifying prostaglandins as high-affinity substrates and NMD-targeted splice variants broadened the substrate repertoire to signaling lipids and revealed a transcript-level regulatory mechanism.

    Evidence Vesicle transport kinetics with RNAi reversal; PTC splice-variant analysis with translation inhibition across species

    PMID:12499391 PMID:12835412

    Open questions at the time
    • Physiological role of prostaglandin efflux not established in vivo
    • NMD contribution to tissue-specific expression unquantified
  5. 2004 High

    A burst of vesicle-kinetic, ATPase, and knockout studies defined the catalytic mechanism, the GSH/cooperative transport modes, and physiological substrates (urate, PAH, bile acids, sulfated steroids), establishing MRP4 as a polyspecific renal/hepatic anion pump under CAR control and a CNS barrier transporter.

    Evidence ATPase and photoaffinity assays, allosteric urate kinetics, PAH vesicle/perfused kidney, Mrp4-KO mice for topotecan CNS exposure, and CAR pharmacology

    PMID:15004017 PMID:15314169 PMID:15364914 PMID:15454390 PMID:15504935

    Open questions at the time
    • No structural model of the catalytic or substrate sites
    • Coupling stoichiometry to ATP not fully resolved
  6. 2004 High

    Localizing MRP4 to platelet subcellular compartments and dense-granule-deficient (Hermansky-Pudlak) platelets first connected the transporter to platelet biology.

    Evidence Immunofluorescence, subcellular fractionation with cGMP transport co-distribution, and patient platelet analysis

    PMID:15297306

    Open questions at the time
    • Dense-granule versus plasma-membrane localization later revised
    • Functional consequence for hemostasis not yet shown
  7. 2005 High

    Demonstrating GSH-coupled bile acid co-transport and urogenital prostanoid transport extended MRP4's physiological role to bile-acid handling and reproductive-tract lipid signaling.

    Evidence Double-labeled vesicle cotransport kinetics; vesicle prostanoid transport with co-localization of biosynthetic enzymes

    PMID:16280858 PMID:16282361

    Open questions at the time
    • In vivo bile-acid handling consequence addressed only later by KO models
    • GSH co-substrate stoichiometry mechanism not structurally explained
  8. 2006 High

    Knockout-mouse pharmacokinetics established MRP4 as the in vivo determinant of renal luminal efflux for antivirals, cephalosporins, and sulfate conjugates, and as the essential protective bile-acid extruder in cholestasis.

    Evidence Mrp4-/- mice with adefovir/tenofovir, cefazolin/ceftizoxime, sulfate-conjugate dosing, and bile-duct ligation injury models

    PMID:16628672 PMID:16988054 PMID:17110501 PMID:17344354

    Open questions at the time
    • Compensatory roles of other MRPs not fully dissected
    • Human cholestasis relevance inferred from mouse
  9. 2008 Medium

    Mutagenesis of TM6 residues and characterization of natural variants mapped substrate-specific determinants and functional polymorphisms, advancing a structural model of the substrate-binding pore.

    Evidence Site-directed mutagenesis (R375, variants G187W/G487E, Y556C/V776I) with vesicle/oocyte transport assays and homology modeling

    PMID:18300232 PMID:18364470 PMID:18612080

    Open questions at the time
    • No experimental atomic structure; binding sites inferred from homology models
    • Clinical impact of variants not established in patients
  10. 2008 Medium

    MRP4 was implicated in dendritic-cell migration, linking efflux activity to immune-cell motility, though the responsible substrate was not identified.

    Evidence Skin-explant migration assays with RNAi and pharmacological inhibition

    PMID:18625884

    Open questions at the time
    • Transported substrate driving DC migration unidentified
    • Single-lab functional assay without in vivo confirmation
  11. 2011 High

    Connecting MRP4-mediated cAMP/cGMP efflux to leukemic differentiation and pulmonary hypertension established MRP4 as a regulator of cyclic-nucleotide signaling with therapeutic targetability.

    Evidence shRNA and probenecid in AML lines; Mrp4-/- and MK571-treated mice in hypoxic PH with PKA/PKG readouts and human tissue

    PMID:21205825 PMID:21403643 PMID:21670499

    Open questions at the time
    • Compartment-specific cAMP gradients not directly imaged here
    • Relative contribution of efflux versus phosphodiesterase not fully separated
  12. 2012 High

    Identifying SNX27-driven endocytosis, CFTR/PDZK1 scaffolding, and biphasic control of cell migration and cardiac contraction defined how MRP4 surface levels are regulated and how local cyclic-nucleotide microdomains transduce its activity.

    Evidence GST pull-down/MS plus co-IP and biotinylation (SNX27); co-IP, FRET-cAMP and CFTR assays; KO fibroblast wound-healing with FRET sensors

    PMID:22381067 PMID:22411990 PMID:22542979 PMID:23264633 PMID:25762723

    Open questions at the time
    • Determinants of compartmentalized cAMP near MRP4 not fully resolved
    • In vivo relevance of CFTR-MRP4 complex beyond colon/heart limited
  13. 2015 High

    Revised super-resolution localization and KO-mouse thrombosis studies established MRP4 as a plasma-membrane platelet regulator of cAMP-PKA signaling that promotes aggregation and thrombus formation, while also redistributing cAMP to dense granules.

    Evidence Plasma-membrane biotinylation, super-resolution microscopy, Abcc4-KO thrombosis/transfusion models, VASP phosphorylation

    PMID:26316625 PMID:26405223

    Open questions at the time
    • Plasma-membrane versus dense-granule localization debate not fully reconciled
    • Molecular link between cAMP efflux and GPVI organization mechanistic detail incomplete
  14. 2018 High

    Identifying S1P as an ATP-dependent MRP4 substrate and its inhibition by statins extended MRP4's role to bioactive sphingolipid secretion from platelets.

    Evidence Vesicle transport with labeled S1P, Abcc4-/- mice, and statin inhibition assays

    PMID:29304533

    Open questions at the time
    • Physiological consequence of altered S1P secretion not phenotyped
    • GSH/co-substrate requirement for S1P transport not addressed
  15. 2019 Medium

    Discovering a transport-independent role in stabilizing β-catenin, alongside cAMP/Epac/Rap1-driven PDAC proliferation, revealed that MRP4 functions in cell signaling both as an efflux pump and as a protein-stabilizing scaffold.

    Evidence shRNA knockdown with co-IP, TOPflash reporter, in vivo uterine knockdown/rescue (endometrium); silencing/overexpression with Epac/Rap1 analysis (PDAC)

    PMID:31043460 PMID:31410201

    Open questions at the time
    • Structural basis of MRP4-β-catenin interaction unknown
    • Generality of transport-independent role beyond endometrium untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MRP4 reconciles its extreme polyspecificity, GSH co-substrate dependence, and allosteric multi-site kinetics within a single defined transport mechanism remains unresolved.
  • No atomic structure of substrate-bound MRP4
  • Mechanistic basis of cooperative/allosteric transport not defined
  • Determinants switching between transport-dependent and transport-independent functions unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 10 GO:0016787 hydrolase activity 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005886 plasma membrane 6 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-382551 Transport of small molecules 4 R-HSA-9748784 Drug ADME 4 R-HSA-1430728 Metabolism 3 R-HSA-109582 Hemostasis 2
Partners
CFTRCTNNB1PDZK1SNX27
Complex memberships
MRP4-CFTR-PDZK1 macromolecular complex

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 MRP4 (ABCC4) mediates ATP-dependent efflux of nucleoside monophosphate analogs PMEA and azidothymidine monophosphate from cells, conferring resistance to antiviral drugs; overexpression and gene amplification correlate with enhanced drug efflux and reduced antiviral efficacy. Drug-selected cell lines with MRP4 overexpression/amplification; chromosome transfer conferring PMEA resistance; ATP-dependent efflux assays Nature medicine High 10470083
1998 MOAT-B (ABCC4/MRP4) encodes a novel ATP-binding cassette transporter closely related to MRP/cMOAT but lacking the ~200 amino acid N-terminal hydrophobic extension; it is ubiquitously expressed with highest levels in prostate. Degenerate PCR cloning; FISH chromosomal mapping to 13q32; Northern blot tissue distribution; protein sequence comparison Cancer research High 9661885
2002 MRP4 localizes to the apical membrane of human kidney proximal tubules and mediates ATP-dependent transport of cAMP and cGMP, with probenecid and dipyridamole as potent inhibitors; MRP4 also transports methotrexate and estradiol-17β-D-glucuronide. Immunolocalization in human kidney; ATP-dependent uptake in inside-out Sf9 membrane vesicles expressing human MRP4; inhibitor studies Journal of the American Society of Nephrology : JASN High 11856762
2003 MRP4 functions as a prostaglandin efflux transporter, mediating ATP-dependent transport of PGE1 and PGE2 (Km ~2-3 µM) in inside-out membrane vesicles; MRP1, MRP2, MRP3, and MRP5 do not transport these prostaglandins; NSAIDs including indomethacin are potent MRP4 inhibitors and block PGE1/PGE2 release from cells. ATP-dependent uptake in inside-out membrane vesicles from insect cells and HEK293 cells expressing MRP4; saturation kinetics; RNAi knockdown; cell accumulation assays with PGT co-expression Proceedings of the National Academy of Sciences of the United States of America High 12835412
2002 MRP4 transports methotrexate, folic acid, and leucovorin with high capacity, low affinity kinetics; addition of a single glutamyl residue to MTX abrogates MRP4-mediated transport, indicating MRP4 is a component of the MTX efflux system alongside MRP1, MRP2, and MRP3. ATP-dependent transport in inside-out membrane vesicles from MRP4-transfected cells; kinetic analysis (Km, Vmax); substrate selectivity studies with polyglutamates Cancer research High 12036927
2004 Mrp4-deficient mice show enhanced topotecan accumulation in brain and CSF; topotecan is an Mrp4 substrate and Mrp4-overexpressing cells are resistant to it. Mrp4 has dual localization at the basolateral membrane of choroid plexus epithelium and apical membrane of brain capillary endothelial cells, limiting drug penetration into the CNS. Mrp4 knockout mice; new antibodies for localization; microdialysis of CSF; cytotoxicity assays; immunohistochemistry Molecular and cellular biology High 15314169
2004 MRP4 transports urate via a positive cooperative mechanism (Km 1.5 mM, Hill coefficient 1.7) with multiple allosteric substrate binding sites; urate stimulates cGMP transport and can be co-transported simultaneously with cAMP or cGMP; MRP4 is proposed as the apical efflux pump for urinary urate excretion. ATP-dependent transport in inside-out membrane vesicles from MRP4-expressing HEK293 cells; kinetic analysis; intracellular accumulation measurements; inhibition/stimulation studies American journal of physiology. Renal physiology High 15454390
2004 MRP4 hydrolyzes ATP (Km 0.62 mM) in a substrate-stimulated manner; prostaglandins E1 and E2 stimulate ATP hydrolysis 2-3 fold; orthovanadate and beryllium fluoride inhibit ATPase activity; MRP4 ATPase is more sensitive to beryllium fluoride than orthovanadate, unlike P-gp; ADP release from the post-hydrolysis transition state may be the rate-limiting step in the catalytic cycle. ATPase activity assays; 8-azido[α-32P]ATP photoaffinity labeling; nucleotide trapping with vanadate and beryllium fluoride; divalent cation studies; expressed in insect cells The Journal of biological chemistry High 15364914
2004 Hepatic Mrp4 and sulfotransferase Sult2a1 are coordinately upregulated by the nuclear receptor CAR; CAR activators increase Mrp4 and Sult2a1 in primary human hepatocytes and HepG2 cells; Sult2a1 is downregulated in Mrp4-null mice, indicating a functional inter-relation between these genes in eliminating sulfated steroids and bile acids. Mrp4 knockout mice; CAR activator treatment; primary human hepatocyte and HepG2 cell studies; Western blot and mRNA analysis The Journal of biological chemistry High 15004017
2005 Human ABCC4 (MRP4) co-transports bile acids (taurine/glycine conjugates and cholate) together with reduced glutathione (GSH) at physiological GSH concentrations; chenodeoxycholyltaurine and chenodeoxycholylglycine are transported with highest affinity (Km 3.6 and 5.9 µM); bile acid-to-GSH transport ratio ~1:22. Inside-out membrane vesicles; double-labeled cotransport experiments; saturation kinetics; substrate specificity screening American journal of physiology. Gastrointestinal and liver physiology High 16282361
2002 MRP4 expression confers resistance to ganciclovir (GCV); MRP4 reduces intracellular accumulation and increases efflux of GCV metabolites; MRP4 overexpression also protects adjacent cells from GCV-mediated bystander killing in HSV-TK gene therapy models. MRP4-overexpressing cell lines; cytotoxicity assays; radiolabeled GCV metabolite accumulation and efflux assays; bystander killing assays The Journal of biological chemistry High 12105214
2002 ABCC4 exports GSH and facilitates cAMP efflux; depletion of intracellular GSH with buthionine sulfoximine decreases cAMP export and increases intracellular cAMP; GSH depletion also reverses ABCC4-mediated resistance to purine analogues PMEA and 6-thioguanine, indicating GSH is required for ABCC4 function. Stable ABCC4-overexpressing cells; GSH depletion with BSO; cAMP efflux measurements; drug resistance and reversal assays The Biochemical journal Medium 11802779
2006 ATP-dependent uptake of adefovir and tenofovir (but not cidofovir) is mediated by MRP4 in membrane vesicles; Mrp4 knockout mice show significantly greater kidney accumulation of adefovir and tenofovir (approximately 2-fold), indicating MRP4 mediates luminal efflux of these drugs in the kidney. ATP-dependent uptake in MRP4-expressing membrane vesicles; Mrp4 knockout mice; constant intravenous infusion; plasma/urine/tissue concentration analysis Molecular pharmacology High 17110501
2006 Mrp4-deficient mice subjected to bile duct ligation show more severe liver injury, lower serum bile acids, and increased taurine tetrahydroxy bile acid levels compared to wild-type; Mrp4 (but not Mrp3) is upregulated after bile duct ligation in wild-type mice, indicating Mrp4 plays a unique and essential protective role in the adaptive response to obstructive cholestatic injury by extruding bile acids from the cholestatic liver. Mrp4-/- mice; common bile duct ligation; histology; serum aminotransferase; Western blot; HPLC bile acid analysis Hepatology (Baltimore, Md.) High 16628672
2004 MRP4 is highly expressed in human platelet dense granules (delta-granules); ATP-dependent cGMP transport co-distributes with MRP4 in subcellular fractions with highest activities in dense granule and plasma membrane fractions; MRP4 is absent in platelets from patients with Hermansky-Pudlak syndrome with defective delta-granules. Immunoblotting; immunofluorescence microscopy with mepacrine as dense granule marker; subcellular fractionation; ATP-dependent cGMP transport; inhibitor studies Blood High 15297306
2007 ABCC4 mediates ATP-dependent efflux of leukotriene B4 (LTB4) in the presence of reduced glutathione (Km ~5 µM), and of LTC4 (Km ~0.13-0.32 µM) without requiring GSH; both transports are inhibited by organic anions including montelukast and MK571. Inside-out membrane vesicles from V79 fibroblasts, Sf9 insect cells (recombinant ABCC4), human platelets, and U937 cells; kinetic analysis; inhibitor profiling The Journal of pharmacology and experimental therapeutics High 17959747
2004 MRP4 transports p-aminohippurate (PAH) with high affinity (Km 160 µM), much higher than MRP2 (Km 2-5 mM); renal cortical MRP4 expression is ~5-fold higher than MRP2, suggesting MRP4 is the primary apical efflux transporter for PAH in the kidney. ATP-dependent PAH uptake in Sf9 membrane vesicles expressing MRP4 and MRP2; isolated perfused kidney from TR(-) rats; kinetic analysis; RT-PCR and Western blot Journal of the American Society of Nephrology : JASN High 15504935
2005 MRP4 is co-expressed with prostanoid-synthesizing enzymes in epithelial cells of human seminal vesicles and mediates ATP-dependent transport of PGE2 (Km 3.5 µM), thromboxane B2 (Km 9.9 µM), and PGF2α (Km 12.6 µM) in the urogenital tract; MRP4 is also localized to the plasma membrane of ureter epithelium, prostate glandular epithelium (basolateral), and smooth muscle cells of bladder and corpus cavernosum. Immunoblot and immunofluorescence; inside-out membrane vesicles with recombinant human MRP4; kinetic analysis of prostanoid transport The Journal of urology High 16280858
2006 Several NSAIDs inhibit MRP4-mediated MTX transport with IC50 values in therapeutically relevant ranges (2 µM to 1.8 mM), generally with higher potency against MRP4 than MRP2; inhibition patterns include one-site and two-site competition models depending on the NSAID; some compounds (phenylbutazone for MRP2, celecoxib for MRP4) show stimulation at low and inhibition at high concentrations. Membrane vesicles from MRP2- and MRP4-overexpressing cells; MTX transport assays; kinetic inhibition modeling The Journal of pharmacology and experimental therapeutics High 17005917
2006 Mrp4 knockout mice show reduced hepatic basolateral excretion of sulfate conjugates (acetaminophen sulfate ~20%, 4-methylumbelliferyl sulfate ~65%, harmol sulfate ~45% reduction); Mrp4 does not contribute to hepatic basolateral excretion of glucuronide conjugates. Abcc4-/- mice; cassette dosing of acetaminophen, 4-methylumbelliferone, and harmol; measurement of glucuronide and sulfate metabolites The Journal of pharmacology and experimental therapeutics High 16988054
2007 MRP4 is involved in the luminal efflux of ceftizoxime (Km 18 µM) and cefazolin (Km 80 µM) in the kidney; Mrp4-/- mice show 2-2.7-fold increased kidney accumulation of these cephalosporins and reduced renal clearance to 7.5-34% of control. ATP-dependent transport in hMRP4-expressing membrane vesicles; constant intravenous infusion in wild-type and Mrp4-/- mice; tissue concentration analysis Molecular pharmacology High 17344354
2008 Ro 64-0802 (active form of oseltamivir) is a substrate of MRP4; MRP4 expression in MDCKII cells increases Ro 64-0802 efflux 3-fold; Mrp4-/- mice show significantly greater brain accumulation of Ro 64-0802 after microinjection and higher Kp,brain after systemic infusion, demonstrating that Mrp4 limits brain distribution by active efflux across the BBB. MDCKII cell efflux assays; Mrp4-/- mice; intracerebral microinjection; continuous subcutaneous infusion; brain/plasma concentration measurements Drug metabolism and disposition High 19029202
2008 Two nonsynonymous MRP4 variants (G187W and G487E) show significantly reduced transport function for AZT and PMEA; G187W also shows decreased protein expression after transfection; other variants show no complete loss of function. Resequencing; site-directed mutagenesis; transient transfection of HEK293T cells; intracellular accumulation assays with AZT and PMEA The Journal of pharmacology and experimental therapeutics Medium 18364470
2008 Arg375 in transmembrane helix 6 of MRP4 contributes to the substrate-binding pocket: R375S mutation reduces MTX affinity but does not affect cGMP transport; restoring positive charge (R375K) restores MTX affinity; MTX inhibition of cGMP transport is noncompetitive; homology modeling places Arg375 and Arg998 in the central aqueous pore. Site-directed mutagenesis of TM helix residues; membrane vesicle transport assays (MTX, cGMP); inhibition kinetics; homology modeling Molecular pharmacology High 18612080
2010 AhR and Nrf2 are key regulators of human MRP4 expression; TCDD, 3-MC, and oltipraz (AhR/Nrf2 activators) increase MRP4 mRNA and protein in HepG2 cells and human hepatocytes; three XRE sites in the MRP4 proximal promoter are required for activity; EMSA and ChIP confirm AhR and Nrf2 bind the MRP4 proximal promoter. Pharmacological induction in HepG2 and primary hepatocytes; luciferase reporter assays; site-directed mutation of XRE sites; EMSA; ChIP American journal of physiology. Gastrointestinal and liver physiology High 20395535
2011 MRP4 regulates intracellular cAMP levels in leukemic cells; extrusion of cAMP is ATP-dependent and probenecid-sensitive; shRNA knockdown of MRP4 increases intracellular cAMP and induces maturation/differentiation of U937 leukemia cells; MRP4 blockade combined with PDE4 inhibition maximally increases cAMP and arrests proliferation. shRNA knockdown; probenecid inhibition; cAMP efflux measurement; proliferation and differentiation assays in U937, HL-60, and KG-1a cells The Journal of biological chemistry High 21205825
2011 Inhibition of MRP4 with MK571 reverses hypoxic pulmonary hypertension in wild-type mice; Mrp4-/- mice are protected from hypoxic PH; MRP4 expression is increased in pulmonary arteries of PAH patients and hypoxic mice; MRP4 inhibition increases intracellular cAMP and cGMP levels and PKA/PKG activities in arterial SMCs. Mrp4-/- mice; hypoxia model; oral MK571 treatment; cyclic nucleotide and PKA/PKG activity measurements; human PAH tissue analysis The Journal of clinical investigation High 21670499
2011 OAT1 mediates uptake of tenofovir into renal proximal tubules while MRP4 mediates its efflux; OAT1 KO prevents tenofovir toxicity, but MRP4 KO leads to increased renal proximal tubular mitochondrial toxicity with TDF treatment, demonstrating both transporters directly regulate tenofovir levels in proximal tubules. OAT1 and MRP4 knockout mice; TDF and ddI treatment; laser-capture microdissection of proximal tubules; mtDNA abundance analysis; electron microscopy Laboratory investigation High 21403643
2012 Sorting nexin 27 (SNX27) interacts with MRP4 via its PDZ-binding motif (identified by GST pull-down and co-IP); SNX27 knockdown increases MRP4 plasma membrane expression, increases 6-MP efflux, and confers resistance; SNX27 promotes endocytosis of MRP4, negatively regulating its cell surface expression and transport function. GST pull-down; MALDI-TOF MS identification of SNX27; co-immunoprecipitation in HEK293 cells; siRNA knockdown; cell surface biotinylation; immunocytochemistry; functional transport assays The Journal of biological chemistry High 22411990
2012 MRP4 localizes to the plasma membrane and, in association with CFTR via the scaffolding protein PDZK1, forms a macromolecular complex; MRP4 inhibition by drugs like AZT or irinotecan increases local cAMP concentration near MRP4-CFTR complexes, activating CFTR-mediated fluid secretion and contributing to drug-induced diarrhea; HIV patients on AZT show augmented MRP4-CFTR complex formation in the colon. Co-immunoprecipitation; FRET-based cAMP measurement; CFTR Cl- secretion assays; colon biopsy analysis from HIV/AZT patients; PDZK1 scaffolding studies The Journal of biological chemistry High 25762723
2012 MRP4-mediated cAMP efflux regulates cell migration in a biphasic manner; Mrp4-/- mouse embryonic fibroblasts have higher intracellular cAMP/cGMP and migrate faster than wild-type; moderate increases in cyclic nucleotides (MRP4 inhibition) enhance migration while robust cAMP increases (forskolin + IBMX) decrease migration. Mrp4-/- mouse embryonic fibroblasts; wound healing assays; FRET-based cAMP and cGMP sensors; MK571 pharmacological inhibition; cell-permeant cyclic nucleotide treatments The Journal of biological chemistry High 23264633
2012 Phe368 of MRP4 transmembrane helix 6 plays a substrate-specific role in transport: F368W mutation causes gain-of-function for E2-17βG and loss-of-function for MTX transport without affecting ATP handling, suggesting Phe368 interacts with substrates during translocation rather than initial binding. Site-directed mutagenesis; membrane vesicle transport assays (E2-17βG, cGMP, MTX, folic acid); substrate docking in homology model of inward- and outward-facing conformations Biochemical pharmacology High 22542979
2012 MRP4 regulates cAMP and β-adrenergic contraction in cardiac myocytes; pharmacological inhibition of MRP4 with MK571 potentiates submaximal isoproterenol-stimulated cAMP accumulation and cardiomyocyte contraction rate via β1-adrenoceptors; MRP4-dependent changes in contraction rate are CFTR-dependent. Neonatal ventricular myocytes; FRET-based cAMP measurement; contraction rate monitoring; β-adrenoceptor and CFTR knockout mice; Western blot European journal of pharmacology Medium 22381067
2013 ABCC4 is regulated by miR-124a and miR-506 through direct binding to its 3'-UTR; these miRNAs decrease MRP4 protein levels 20-30% and reduce MRP4 function by 50% without affecting mRNA; miR-124a and miR-506 expression is negatively correlated with MRP4 protein in human kidney samples; mutation of the binding site eliminates miRNA regulation. miRNA mimic transfection in HEK293T/17; Western blot; functional transport assays; luciferase reporter assays with 3'-UTR; 3'-UTR mutation; correlation analysis in 26 human kidney samples Biochemical pharmacology High 24184504
2013 MRP4 inhibition in trabecular meshwork cells increases intracellular cAMP and cGMP, causes cell relaxation via cGMP-dependent PKG signaling, reduces actin stress fibers and MLC phosphorylation; topical MK571 significantly decreases intraocular pressure in rabbits, indicating MRP4 regulates aqueous humor outflow and IOP. RT-PCR, immunoblot, immunofluorescence in human TM cells; ELISA for cAMP/cGMP; siRNA knockdown; PKA/PKG/Rho GTPase activity assays; topical application in rabbit eyes Investigative ophthalmology & visual science High 23385799
2014 Human MRP4 mediates ATP-dependent export of dimethylarsinic acid (DMAV) and the diglutathione conjugate of monomethylarsonous acid [MMA(GS)2]; transport is allosteric (Hill coefficients >1), high-affinity (K0.5 0.70 µM for MMA(GS)2; 0.22 µM for DMAV), and pH-dependent; MRP3 and MRP5 do not transport these arsenicals. HEK293 cell cytotoxicity and accumulation assays; inside-out membrane vesicle transport assays with MRP4-enriched vesicles; kinetic and pH analyses; comparison with MRP3 and MRP5 Molecular pharmacology High 24870404
2015 ABCC4 (MRP4) is expressed primarily on the plasma membrane (not dense granules) of mouse and human platelets as shown by plasma membrane biotinylation and super-resolution microscopy; Abcc4 KO platelets have impaired collagen-induced aggregation, reduced GPVI localization at plasma membrane, and elevated intracellular cAMP; Abcc4 KO mice show impaired thrombus formation in vivo; MRP4 promotes platelet aggregation by modulating the cAMP-PKA signaling pathway. Plasma membrane biotinylation; super-resolution microscopy; Abcc4 knockout mice; ferric-chloride thrombosis model; platelet aggregation; integrin activation; flow adhesion assays; GPVI localization; cAMP measurement; VASP phosphorylation Blood High 26405223
2015 MRP4 redistributes cAMP from the cytosol to dense granules in platelets; Mrp4-/- mice show delayed arterial occlusion, prolonged bleeding time, and defective platelet activation in vitro; impaired thrombus formation in MRP4-deficient platelet transfusion model confirms platelet-specific role; increased VASP phosphorylation in MRP4-/- platelets indicates elevated cytosolic cAMP. MRP4-/- mice; tail bleeding time; ferric chloride arterial occlusion; platelet depletion/transfusion model; flow-based adhesion; aggregation assays; VASP phosphorylation (cAMP readout); dense granule number/volume analysis Blood High 26316625
2016 ABCC4 is a determinant of cytarabine-induced cytotoxicity; cytarabine and its monophosphate are transported by ABCC4-expressing vesicles; overexpression of ABCC4 impairs cytarabine intracellular retention; Abcc4-null mice show enhanced cytarabine-induced hematological toxicity and sensitized myeloid progenitors ex vivo. ABCC4-expressing vesicle transport assays; ABCC4-overexpressing and siRNA-silenced cells; cytotoxicity assays with MK571/sorafenib; Abcc4-null mice; ex vivo colony-forming assays Clinical and translational science High 26842729
2018 MRP4 (ABCC4) mediates ATP-dependent transport of sphingosine-1-phosphate (S1P) in platelet membrane vesicles and Sf9 vesicles; MRP4-deficient mice show reduced agonist-induced S1P secretion and lower platelet S1P concentrations; statins (fluvastatin, rosuvastatin) inhibit MRP4-mediated S1P transport and cGMP uptake in vesicles. Vesicle transport assays (fluorescein- and tritium-labeled S1P); MRP4-/- mice; confocal microscopy; MRP inhibitor (MK571, ceefourin-1); statin inhibition assays Thrombosis and haemostasis High 29304533
2019 MRP4 knockdown (but not transport-function inhibition) accelerates β-catenin degradation in human endometrial cells; MRP4 and β-catenin co-localize and co-immunoprecipitate in mouse and human endometrium; MRP4 knockdown in mouse uterus reduces β-catenin, downregulates Wnt/β-catenin target genes, and impairs embryo implantation — all reversed by blocking β-catenin degradation — revealing a transport-independent role of MRP4 in stabilizing β-catenin. shRNA knockdown in human endometrial cells; immunoprecipitation; immunoblotting; immunofluorescence; TOPflash reporter assay; in vivo mouse uterine knockdown; qPCR array; in vitro and in vivo tumorigenesis assays Theranostics High 31410201
2019 MRP4-dependent cAMP efflux drives cell proliferation in pancreatic ductal adenocarcinoma (PDAC) cells through the cAMP/Epac/Rap1 signaling pathway; MRP4 silencing reduces proliferation and overexpression increases it; extracellular cAMP reverses the antiproliferative effect of MRP4 blockade; pharmacological inhibition (probenecid, MK571, ceefourin-1) also reduces proliferation. MRP4 silencing (siRNA) and overexpression; pharmacological inhibition; cAMP efflux measurement; Epac/Rap1 pathway analysis; in vitro proliferation assays Molecular pharmacology Medium 31043460
2003 The ABCC4 gene contains conserved alternatively spliced exons encoding premature termination codons (PTCs) that are targets of nonsense-mediated mRNA decay (NMD); protein synthesis inhibition stabilizes PTC-containing ABCC4 transcripts; NMD serves as a regulatory mechanism controlling ABCC4 expression, conserved across human, monkey, and rodent. ABCC4 gene structure determination; identification of PTC-containing splice variants; protein synthesis inhibition in cell lines; mRNA stability analysis in human, monkey, and rodent cells Human molecular genetics Medium 12499391
2008 MRP4 contributes to dendritic cell migration from human skin; pharmacological inhibition of MRP4 or RNAi knockdown reduces DC migration from skin explants and in vitro-generated Langerhans cells; the responsible MRP4 substrate mediating DC migration was not identified in this study. Human skin explant migration assay; RNAi knockdown of MRP4 in DCs; pharmacological inhibition; in vitro Langerhans cell generation; exogenous substrate rescue experiments Blood Medium 18625884
2008 Two MRP4 missense variants Y556C (Walker B motif) and V776I (transmembrane domain) alter transport function: V776I shows significantly reduced 6-MP transport, Y556C shows significantly higher PMEA transport compared to wild-type MRP4 expressed in Xenopus laevis oocytes. Site-directed mutagenesis; Xenopus laevis oocyte expression; radiolabeled 6-MP and PMEA transport; localization by fluorescence microscopy Human mutation Medium 18300232
2010 MRP4 is absent in platelets of two patients with a delta-storage pool deficiency (delta-SPD)-like phenotype with selectively reduced platelet adenine nucleotide storage but normal serotonin levels; MRP4 is present in their lymphocytes and the ABCC4 coding region shows no mutation, suggesting a post-transcriptional defect; this identifies a delta-SPD phenotype associated with absent platelet MRP4. Immunoblotting and immunofluorescence in patient platelets and lymphocytes; ABCC4 gene sequencing; comparison with classic delta-SPD (low AN and serotonin) The American journal of pathology Medium 20133816
2013 Abcc4 teams with Abcb1a/b and Abcg2 to form a cooperative efflux system limiting brain penetration of camptothecin analogues (topotecan, irinotecan, SN-38, gimatecan); in Abcb1a/b;Abcg2 double KO mice, additional Abcc4 deficiency increases brain concentration up to 5.8-fold (SN-38); Abcc4 alone is sufficient to reduce SN-38 brain concentration to WT levels. Triple KO mice (Abcb1a/b;Abcg2;Abcc4); multiple drug brain concentration measurements by HPLC; elacridar combination treatment Clinical cancer research High 23461902

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nature medicine 458 10470083
2003 The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proceedings of the National Academy of Sciences of the United States of America 403 12835412
2002 The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP. Journal of the American Society of Nephrology : JASN 377 11856762
2004 Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Molecular and cellular biology 331 15314169
2008 Multidrug resistance protein 4 (MRP4/ABCC4): a versatile efflux transporter for drugs and signalling molecules. Trends in pharmacological sciences 325 18353444
2002 Analysis of methotrexate and folate transport by multidrug resistance protein 4 (ABCC4): MRP4 is a component of the methotrexate efflux system. Cancer research 270 12036927
2006 Functional involvement of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the renal elimination of the antiviral drugs adefovir and tenofovir. Molecular pharmacology 215 17110501
2004 Interactions between hepatic Mrp4 and Sult2a as revealed by the constitutive androstane receptor and Mrp4 knockout mice. The Journal of biological chemistry 193 15004017
2004 Human organic anion transporter MRP4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric substrate binding sites. American journal of physiology. Renal physiology 189 15454390
2006 Interaction of nonsteroidal anti-inflammatory drugs with multidrug resistance protein (MRP) 2/ABCC2- and MRP4/ABCC4-mediated methotrexate transport. The Journal of pharmacology and experimental therapeutics 181 17005917
2006 Mrp4-/- mice have an impaired cytoprotective response in obstructive cholestasis. Hepatology (Baltimore, Md.) 136 16628672
2011 Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation. The Journal of biological chemistry 132 21205825
2004 The nucleotide transporter MRP4 (ABCC4) is highly expressed in human platelets and present in dense granules, indicating a role in mediator storage. Blood 132 15297306
2011 Tenofovir renal proximal tubular toxicity is regulated by OAT1 and MRP4 transporters. Laboratory investigation; a journal of technical methods and pathology 129 21403643
2005 Substrate specificity of human ABCC4 (MRP4)-mediated cotransport of bile acids and reduced glutathione. American journal of physiology. Gastrointestinal and liver physiology 123 16282361
2005 Cellular export of drugs and signaling molecules by the ATP-binding cassette transporters MRP4 (ABCC4) and MRP5 (ABCC5). Drug metabolism reviews 122 15747503
2004 Contribution of multidrug resistance protein 2 (MRP2/ABCC2) to the renal excretion of p-aminohippurate (PAH) and identification of MRP4 (ABCC4) as a novel PAH transporter. Journal of the American Society of Nephrology : JASN 114 15504935
1998 Isolation of MOAT-B, a widely expressed multidrug resistance-associated protein/canalicular multispecific organic anion transporter-related transporter. Cancer research 113 9661885
2002 Role of glutathione in the multidrug resistance protein 4 (MRP4/ABCC4)-mediated efflux of cAMP and resistance to purine analogues. The Biochemical journal 106 11802779
2002 Expression of MRP4 confers resistance to ganciclovir and compromises bystander cell killing. The Journal of biological chemistry 106 12105214
2007 Expression of bile acid synthesis and detoxification enzymes and the alternative bile acid efflux pump MRP4 in patients with primary biliary cirrhosis. Liver international : official journal of the International Association for the Study of the Liver 101 17696930
2007 ATP-dependent transport of leukotrienes B4 and C4 by the multidrug resistance protein ABCC4 (MRP4). The Journal of pharmacology and experimental therapeutics 96 17959747
2008 Limited brain distribution of [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), a pharmacologically active form of oseltamivir, by active efflux across the blood-brain barrier mediated by organic anion transporter 3 (Oat3/Slc22a8) and multidrug resistance-associated protein 4 (Mrp4/Abcc4). Drug metabolism and disposition: the biological fate of chemicals 90 19029202
2008 The human multidrug resistance protein 4 (MRP4, ABCC4): functional analysis of a highly polymorphic gene. The Journal of pharmacology and experimental therapeutics 89 18364470
2011 Inhibition of MRP4 prevents and reverses pulmonary hypertension in mice. The Journal of clinical investigation 88 21670499
2002 Role of MRP4 and MRP5 in biology and chemotherapy. AAPS pharmSci 81 12423063
2007 Substrate overlap between Mrp4 and Abcg2/Bcrp affects purine analogue drug cytotoxicity and tissue distribution. Cancer research 76 17638908
2006 Evaluation of the role of multidrug resistance-associated protein (Mrp) 3 and Mrp4 in hepatic basolateral excretion of sulfate and glucuronide metabolites of acetaminophen, 4-methylumbelliferone, and harmol in Abcc3-/- and Abcc4-/- mice. The Journal of pharmacology and experimental therapeutics 75 16988054
2010 Aryl hydrocarbon receptor and NF-E2-related factor 2 are key regulators of human MRP4 expression. American journal of physiology. Gastrointestinal and liver physiology 72 20395535
2005 Prostanoid transport by multidrug resistance protein 4 (MRP4/ABCC4) localized in tissues of the human urogenital tract. The Journal of urology 72 16280858
2004 Multidrug resistance protein 4 (MRP4/ABCC4) mediates efflux of bimane-glutathione. The international journal of biochemistry & cell biology 69 14643890
2007 Variability in human hepatic MRP4 expression: influence of cholestasis and genotype. The pharmacogenomics journal 65 17404579
2007 Involvement of MRP4 (ABCC4) in the luminal efflux of ceftizoxime and cefazolin in the kidney. Molecular pharmacology 64 17344354
2007 Physiological and pharmacological functions of Mrp2, Mrp3 and Mrp4 as determined from recent studies on gene-disrupted mice. Cancer metastasis reviews 62 17273943
2008 Androgen regulation of multidrug resistance-associated protein 4 (MRP4/ABCC4) in prostate cancer. The Prostate 58 18615486
2005 Interactions of mefloquine with ABC proteins, MRP1 (ABCC1) and MRP4 (ABCC4) that are present in human red cell membranes. Biochemical pharmacology 57 16004972
2004 Rat multidrug resistance protein 4 (Mrp4, Abcc4): molecular cloning, organ distribution, postnatal renal expression, and chemical inducibility. Biochemical and biophysical research communications 49 15047146
2008 A role for multidrug resistance protein 4 (MRP4; ABCC4) in human dendritic cell migration. Blood 48 18625884
2003 Nonsense mediated decay downregulates conserved alternatively spliced ABCC4 transcripts bearing nonsense codons. Human molecular genetics 48 12499391
2020 Apigenin by targeting hnRNPA2 sensitizes triple-negative breast cancer spheroids to doxorubicin-induced apoptosis and regulates expression of ABCC4 and ABCG2 drug efflux transporters. Biochemical pharmacology 47 33011162
2008 6-mercaptopurine and 9-(2-phosphonyl-methoxyethyl) adenine (PMEA) transport altered by two missense mutations in the drug transporter gene ABCC4. Human mutation 47 18300232
2017 Multiple drug resistance-associated protein (MRP4) exports prostaglandin E2 (PGE2) and contributes to metastasis in basal/triple negative breast cancer. Oncotarget 46 28029661
2014 Multiple drug resistance-associated protein 4 (MRP4), prostaglandin transporter (PGT), and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) as determinants of PGE2 levels in cancer. Prostaglandins & other lipid mediators 46 25433169
2013 Clinicopathological impact of ABCC1/MRP1 and ABCC4/MRP4 in epithelial ovarian carcinoma. BioMed research international 45 24024181
2017 Interaction between NUDT15 and ABCC4 variants enhances intolerability of 6-mercaptopurine in Japanese patients with childhood acute lymphoblastic leukemia. The pharmacogenomics journal 44 28418010
2014 ABCC4 copy number variation is associated with susceptibility to esophageal squamous cell carcinoma. Carcinogenesis 44 24510239
2012 Expression of genes involved in xenobiotic metabolism and transport in end-stage liver disease: up-regulation of ABCC4 and CYP1B1. Pharmacological reports : PR 44 23087145
2004 Multidrug resistance protein 4 (ABCC4)-mediated ATP hydrolysis: effect of transport substrates and characterization of the post-hydrolysis transition state. The Journal of biological chemistry 44 15364914
2002 Therapeutic and biological importance of getting nucleotides out of cells: a case for the ABC transporters, MRP4 and 5. Advanced drug delivery reviews 44 12406648
2019 MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer. Theranostics 43 31410201
2016 MRP4 (ABCC4) as a potential pharmacologic target for cardiovascular disease. Pharmacological research 43 27063943
2009 Hematopoietic stem cell differentiation affects expression and function of MRP4 (ABCC4), a transport protein for signaling molecules and drugs. International journal of cancer 43 19142964
2015 Impaired platelet activation and cAMP homeostasis in MRP4-deficient mice. Blood 42 26316625
2007 Evaluation of the role of breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance-associated protein 4 (MRP4/ABCC4) in the urinary excretion of sulfate and glucuronide metabolites of edaravone (MCI-186; 3-methyl-1-phenyl-2-pyrazolin-5-one). Drug metabolism and disposition: the biological fate of chemicals 42 17682070
2013 Abcc4 together with abcb1 and abcg2 form a robust cooperative drug efflux system that restricts the brain entry of camptothecin analogues. Clinical cancer research : an official journal of the American Association for Cancer Research 40 23461902
2011 Changes of organic anion transporter MRP4 and related nuclear receptors in human obstructive cholestasis. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 40 21359593
2011 The ABCC4 gene is a promising target for pancreatic cancer therapy. Gene 40 21989485
2015 The ABCC4 membrane transporter modulates platelet aggregation. Blood 39 26405223
2009 Silencing MRP4 by small interfering RNA reverses acquired DDP resistance of gastric cancer cell. Cancer letters 39 19883972
2012 ABCC4/MRP4: a MYCN-regulated transporter and potential therapeutic target in neuroblastoma. Frontiers in oncology 38 23267433
2008 Functional role of arginine 375 in transmembrane helix 6 of multidrug resistance protein 4 (MRP4/ABCC4). Molecular pharmacology 38 18612080
2014 ABCC4 is required for cell proliferation and tumorigenesis in non-small cell lung cancer. OncoTargets and therapy 37 24591841
2014 Prostaglandin transporters ABCC4 and SLCO2A1 in the uterine endometrium and conceptus during pregnancy in pigs. Biology of reproduction 37 24695625
2015 Influence of ABCC2 and ABCC4 polymorphisms on tenofovir plasma concentrations in Thai HIV-infected patients. Antimicrobial agents and chemotherapy 36 25801567
2014 A novel pathway for arsenic elimination: human multidrug resistance protein 4 (MRP4/ABCC4) mediates cellular export of dimethylarsinic acid (DMAV) and the diglutathione conjugate of monomethylarsonous acid (MMAIII). Molecular pharmacology 36 24870404
2010 Role of MRP4 (ABCC4) in platelet adenine nucleotide-storage: evidence from patients with delta-storage pool deficiencies. The American journal of pathology 36 20133816
2013 ABCC4 is regulated by microRNA-124a and microRNA-506. Biochemical pharmacology 34 24184504
2016 Polymorphic variants of MRP4/ABCC4 differentially modulate the transport of methylated arsenic metabolites and physiological organic anions. Biochemical pharmacology 31 27659809
2009 Construction of triple-transfected cells [organic anion-transporting polypeptide (OATP) 1B1/multidrug resistance-associated protein (MRP) 2/MRP3 and OATP1B1/MRP2/MRP4] for analysis of the sinusoidal function of MRP3 and MRP4. Drug metabolism and disposition: the biological fate of chemicals 31 19628752
2006 Hormonal regulation of renal multidrug resistance-associated proteins 3 and 4 (Mrp3 and Mrp4) in mice. Biochemical pharmacology 31 16529719
2012 Sorting nexin 27 interacts with multidrug resistance-associated protein 4 (MRP4) and mediates internalization of MRP4. The Journal of biological chemistry 30 22411990
2020 Identification of the ABCC4, IER3, and CBFA2T2 candidate genes for resistance to paratuberculosis from sequence-based GWAS in Holstein and Normande dairy cattle. Genetics, selection, evolution : GSE 29 32183688
2017 A polymorphism in ABCC4 is related to efficacy of 5-FU/capecitabine-based chemotherapy in colorectal cancer patients. Scientific reports 29 28765596
2015 Compartmentalized accumulation of cAMP near complexes of multidrug resistance protein 4 (MRP4) and cystic fibrosis transmembrane conductance regulator (CFTR) contributes to drug-induced diarrhea. The Journal of biological chemistry 29 25762723
2014 Genetic variability in key genes in prostaglandin E2 pathway (COX-2, HPGD, ABCC4 and SLCO2A1) and their involvement in colorectal cancer development. PloS one 29 24694755
2012 Multi-drug resistance protein 4 (MRP4)-mediated regulation of fibroblast cell migration reflects a dichotomous role of intracellular cyclic nucleotides. The Journal of biological chemistry 29 23264633
2003 Overexpression of mutated MRP4 in cisplatin resistant small cell lung cancer cell line: collateral sensitivity to azidothymidine. International journal of oncology 28 12792791
2020 Roles of ABCC1 and ABCC4 in Proliferation and Migration of Breast Cancer Cell Lines. International journal of molecular sciences 27 33081264
2010 Sustained repression and translocation of Ntcp and expression of Mrp4 for cholestasis after rat 90% partial hepatectomy. Journal of hepatology 27 21167233
2018 Release of Platelet-Derived Sphingosine-1-Phosphate Involves Multidrug Resistance Protein 4 (MRP4/ABCC4) and Is Inhibited by Statins. Thrombosis and haemostasis 26 29304533
2016 ABCC4 Is a Determinant of Cytarabine-Induced Cytotoxicity and Myelosuppression. Clinical and translational science 26 26842729
2014 Upregulation of COX-2 in the lung cancer promotes overexpression of multidrug resistance protein 4 (MRP4) via PGE2-dependent pathway. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 26 24909729
2013 Multidrug resistance protein 4 (MRP4) expression in prostate cancer is associated with androgen signaling and decreases with tumor progression. Virchows Archiv : an international journal of pathology 26 23503867
2012 MRP4 and CFTR in the regulation of cAMP and β-adrenergic contraction in cardiac myocytes. European journal of pharmacology 26 22381067
2019 Dual-Targeting of miR-124-3p and ABCC4 Promotes Sensitivity to Adriamycin in Breast Cancer Cells. Genetic testing and molecular biomarkers 25 30807260
2014 Identification of new MRP4 inhibitors from a library of FDA approved drugs using a high-throughput bioluminescence screen. Biochemical pharmacology 25 25462817
2014 Silencing of the ABCC4 gene by RNA interference reverses multidrug resistance in human gastric cancer. Oncology reports 25 25572969
2013 MRP4-mediated regulation of intracellular cAMP and cGMP levels in trabecular meshwork cells and homeostasis of intraocular pressure. Investigative ophthalmology & visual science 25 23385799
2019 Inhibition of MRP4 alleviates sepsis-induced acute lung injury in rats. International immunopharmacology 24 30995593
2016 Enhanced platelet MRP4 expression and correlation with platelet function in patients under chronic aspirin treatment. Thrombosis and haemostasis 24 27683757
2014 Characterization of zebrafish Abcc4 as an efflux transporter of organochlorine pesticides. PloS one 24 25478949
2014 Overexpression of MRP4 (ABCC4) and MRP5 (ABCC5) confer resistance to the nucleoside analogs cytarabine and troxacitabine, but not gemcitabine. SpringerPlus 24 25674464
2017 Investigation of the Importance of Multidrug Resistance-Associated Protein 4 (Mrp4/Abcc4) in the Active Efflux of Anionic Drugs Across the Blood-Brain Barrier. Journal of pharmaceutical sciences 23 28456721
2020 Multidrug resistance protein 4 (MRP4/ABCC4) is overexpressed in clear cell renal cell carcinoma (ccRCC) and is essential to regulate cell proliferation. International journal of biological macromolecules 22 32553977
2019 Functional Expression of Multidrug Resistance Protein 4 MRP4/ABCC4. SLAS discovery : advancing life sciences R & D 22 31381460
2018 Discovery of novel multidrug resistance protein 4 (MRP4) inhibitors as active agents reducing resistance to anticancer drug 6-Mercaptopurine (6-MP) by structure and ligand-based virtual screening. PloS one 22 30321196
2016 Multidrug resistance-associated protein 4 (MRP4) controls ganciclovir intracellular accumulation and contributes to ganciclovir-induced neutropenia in renal transplant patients. Pharmacological research 22 27402191
2015 The overexpression of MRP4 is related to multidrug resistance in osteosarcoma cells. Journal of cancer research and therapeutics 22 25879330
2012 Phenylalanine 368 of multidrug resistance-associated protein 4 (MRP4/ABCC4) plays a crucial role in substrate-specific transport activity. Biochemical pharmacology 22 22542979
2019 Identification of MRP4/ABCC4 as a Target for Reducing the Proliferation of Pancreatic Ductal Adenocarcinoma Cells by Modulating the cAMP Efflux. Molecular pharmacology 21 31043460

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