{"gene":"ABCC1","run_date":"2026-06-09T22:02:36","timeline":{"discoveries":[{"year":2022,"finding":"ABCC1 directly exports cyclic GMP-AMP (cGAMP) in an ATP-dependent manner. ABCC1 overexpression enhanced cGAMP export and limited STING signaling, while ABCC1 loss reduced cGAMP export and potentiated STING signaling. ABCC1 deficiency exacerbated cGAS-dependent autoimmunity in Trex1-/- mice, establishing ABCC1-mediated cGAMP export as a key regulatory mechanism limiting cell-intrinsic STING activation.","method":"Overexpression and loss-of-function studies in mouse and human cells, cGAMP export assays, Trex1-/- mouse model epistasis","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function with defined molecular phenotype (cGAMP export, STING signaling), replicated in mouse model with autoimmune disease endpoint","pmids":["36070769"],"is_preprint":false},{"year":1996,"finding":"MRP1/ABCC1 (GS-X pump) transports both leukotriene C4 (LTC4) and the glutathione-platinum complex (GS-Pt) in an ATP-dependent manner. Glutathione-platinum complex, but not cisplatin itself, competitively inhibited ATP-dependent LTC4 transport in membrane vesicles from MRP1-overexpressing cells, indicating a shared binding site.","method":"ATP-dependent transport assays in plasma membrane vesicles from MRP1-overexpressing cells; competitive inhibition kinetics","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro transport reconstitution in membrane vesicles with competitive inhibition kinetics; replicated across multiple labs subsequently","pmids":["8663001"],"is_preprint":false},{"year":2010,"finding":"ABCC1 exports sphingosine 1-phosphate (S1P) and dihydro-S1P from breast cancer cells. Estradiol-induced S1P export required estrogen receptor-alpha and was suppressed by pharmacological inhibitors or siRNA knockdown of ABCC1. This ABCC1-mediated S1P export activated ERK1/2 signaling downstream.","method":"Pharmacological inhibition and siRNA knockdown of ABCC1, S1P export measurement, ERK1/2 phosphorylation assays in MCF-7 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown and inhibitor studies with defined molecular readout (S1P export, ERK activation), single lab","pmids":["20110355"],"is_preprint":false},{"year":2018,"finding":"ABCC1-exported S1P (produced by SphK1) promotes breast cancer tumor growth, angiogenesis, lymphangiogenesis, metastasis, and upregulates SphK1 transcription in a feed-forward manner. Overexpression of ABCC1 (but not ABCB1) in breast cancer cells enhanced S1P secretion, proliferation, migration, and tumor growth in mouse mammary fat pad implantation models.","method":"ABCC1 overexpression in MCF-7 and 4T1 cells, in vivo mammary fat pad tumor implantation, S1P secretion measurement","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro gain-of-function with defined molecular and phenotypic readouts, single lab","pmids":["29523764"],"is_preprint":false},{"year":1998,"finding":"Doxorubicin- and daunorubicin-glutathione conjugates (but not unconjugated drugs) competitively inhibit LTC4 transport by MRP1/GS-X pump, with Ki values of 60–200 nM, indicating that glutathionation enables anthracycline recognition at the shared substrate-binding site of ABCC1.","method":"In vitro LTC4 transport assay using MRP1-overexpressing membrane vesicles; competitive inhibition kinetics with synthesized GS-conjugates","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with competitive inhibition kinetics, chemically defined substrates, replicated concept","pmids":["9647783"],"is_preprint":false},{"year":2011,"finding":"Notch1 intracellular domain (N1IC) transcriptionally upregulates ABCC1/MRP1 expression via the transcription factor CBF1 binding to specific sites in the ABCC1 promoter. Reducing N1IC (by γ-secretase inhibitor or shRNA) decreased ABCC1 expression; ectopic N1IC increased ABCC1 and drug resistance. ChIP and gel-shift assays confirmed N1IC-activated CBF1 interaction with the ABCC1 promoter; mutation of CBF1 binding sites attenuated promoter activity.","method":"γ-secretase inhibitor and shRNA knockdown, ectopic overexpression, ABCC1 promoter-reporter assay, ChIP, gel-shift (EMSA), site-directed mutagenesis of CBF1 binding sites","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, EMSA, promoter mutagenesis, genetic knockdown/overexpression) in one study","pmids":["22143792"],"is_preprint":false},{"year":2014,"finding":"NOTCH1 intracellular domain (ICN1) directly binds to the promoter region of ABCC1 to transactivate its expression in prostate cancer stem cells, resulting in enhanced chemoresistance. ChIP-PCR confirmed ICN1 occupancy at the ABCC1 promoter; shRNA knockdown of NOTCH1 decreased ABCC1 expression and improved chemosensitivity.","method":"ChIP-PCR, shRNA knockdown, quantitative RT-PCR, Western blot, MTT chemosensitivity assay","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-PCR and knockdown with functional readout, single lab","pmids":["24782036"],"is_preprint":false},{"year":2004,"finding":"Proline residues in transmembrane helices 6, 8, 10, 11 (MSD2) and 14 (MSD3) of MRP1/ABCC1 are critical for organic anion transport function. Ala substitution of TM6-Pro343, TM8-Pro448, TM10-Pro557, TM11-Pro595, and TM14-Pro1088 significantly reduced transport of five organic anion substrates. Pro1150 in cytoplasmic loop 7 (CL7) differentially modulates substrate-specific transport and ATP dependence.","method":"Alanine-scanning mutagenesis of 18 Pro residues; vesicular transport assays for multiple organic anion substrates; ATP binding studies in HEK cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis combined with in vitro transport reconstitution across multiple substrates in one study","pmids":["14722114"],"is_preprint":false},{"year":2010,"finding":"Cytoplasmic loop 5 (CL5) of MRP1/ABCC1 is critical for plasma membrane expression and transport function. Ala substitution of conserved charged residues Lys513, Lys516, Glu521, and Glu535 markedly reduced MRP1 protein levels; NBD2 residues His1364 and Arg1367 at the CL5 interface also reduced MRP1 levels, indicating a critical role for the CL5-NBD2 interface in membrane expression. Gly511 mutation reduced vanadate-induced ADP trapping, indicating altered catalytic activity without affecting ATP binding.","method":"Site-directed mutagenesis, immunoblotting, plasma membrane expression assays, 32P-azido-ATP binding and vanadate-induced trapping assays, vesicular transport assays in HEK cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis with multiple orthogonal biochemical readouts (expression, ATPase, transport) in one study","pmids":["21177244"],"is_preprint":false},{"year":2012,"finding":"Glu521 and Glu535 in CL5 of MRP1/ABCC1 are differentially required for proper interdomain folding and transport function. E521A and E535A mutants misfold and are degraded by the proteasome; chemical chaperone 4-PBA rescues plasma membrane expression of both but reveals distinct conformational defects: E535A shows reduced substrate affinity affecting both halves of the transporter, while E521A shows altered ATP interactions and a distinct conformational change in the COOH-proximal half.","method":"Site-directed mutagenesis, proteasome inhibitor and chemical chaperone rescue (4-PBA), immunoblotting, confocal microscopy, vesicular transport assays, conformational antibody studies in HEK cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis with multiple orthogonal rescue and functional analyses revealing differential domain-specific folding requirements","pmids":["22232552"],"is_preprint":false},{"year":2008,"finding":"Transmembrane helices 8 and 9 and portions of cytoplasmic loops 4 and 5 of MRP1/ABCC1 (particularly Tyr440) are critical for binding and transport of glutathione conjugates including LTC4. Substitution of Tyr440 with Phe (as in MRP3) reduced LTC4 and GSH-stimulated estrone-3-sulfate transport by increasing Km for LTC4 5-fold and substantially reducing photolabeling by [3H]LTC4 and azidophenacyl-[35S]GSH.","method":"MRP1/MRP3 chimeric protein construction, site-directed mutagenesis, vesicular transport assays, photoaffinity labeling with [3H]LTC4 and azidophenacyl-[35S]GSH","journal":"Drug metabolism and disposition: the biological fate of chemicals","confidence":"High","confidence_rationale":"Tier 1 / Strong — chimeric protein mapping combined with point mutagenesis and photoaffinity labeling, multiple substrates tested","pmids":["18775981"],"is_preprint":false},{"year":2016,"finding":"ABCC1 exports corticosterone but not cortisol, whereas ABCB1 exports cortisol but not corticosterone. ABCC1 (but not ABCB1) is expressed in human adipose tissue; ABCC1 inhibition with probenecid or Abcc1 knockout in mice increased intracellular corticosterone but not cortisol in adipose, sufficient to induce glucocorticoid-responsive gene transcription.","method":"ABCC1 pharmacological inhibition (probenecid), Abcc1 knockout mice, corticosteroid infusion in adrenalectomized animals, mass spectrometry measurement of steroid concentrations, glucocorticoid-responsive gene expression in adipose","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout and pharmacological inhibition with orthogonal steroid measurement and gene expression readouts, replicated across mouse models and human adipocytes","pmids":["27535620"],"is_preprint":false},{"year":2016,"finding":"Phosphorylation of Tyr920/Ser921 and N-linked glycosylation at Asn19/Asn23 of MRP1/ABCC1 selectively modify As(GS)3 transport kinetics. Phosphorylation-mimicking double mutation Tyr920/Ser921 switches MRP1 to a lower-affinity, higher-capacity As(GS)3 transporter; glycosylation at Asn19/Asn23 increases substrate affinity. Cross-talk between these two modifications was demonstrated: phosphorylation-mimicking substitutions abrogated the effect of Asn19/23Gln glycosylation on As(GS)3 kinetics.","method":"Site-directed mutagenesis of glycosylation (N19Q, N23Q, N1006Q) and phosphorylation (Y920F, S921A, and combinations) sites; membrane vesicle transport assays with As(GS)3; prepared with/without phosphatase inhibitors in HEK293 and HeLa cells","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis of PTM sites with in vitro transport kinetics in two cell lines, phosphatase inhibitor controls, and epistatic double-mutant analysis","pmids":["27297967"],"is_preprint":false},{"year":2005,"finding":"MRP1/ABCC1 Ala989Thr (SNP) causes a significant decrease in estradiol 17β-glucuronide transport due to decreased apparent affinity (increased Km), as determined by vesicular transport assays in HEK cells transfected with site-directed mutants. Nine other naturally occurring missense variants did not substantially alter transport function.","method":"Site-directed mutagenesis recreating 10 SNPs, transient transfection in HEK cells, vesicular transport assays, immunoblotting","journal":"Pharmacogenetics and genomics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro transport reconstitution with mutagenesis, single lab","pmids":["16041243"],"is_preprint":false},{"year":2012,"finding":"Collagen/β1 integrin signaling upregulates ABCC1 expression and function via the ERK/MAPK pathway and requires actin polymerization. Inhibition or knockdown of ABCC1 prevented collagen-mediated reduction of intracellular doxorubicin and collagen-mediated protection from doxorubicin-induced apoptosis in leukemic T-cells.","method":"β1 integrin signaling with collagen/fibronectin, ERK inhibitor and siRNA knockdown, ABCC1 knockdown, intracellular doxorubicin measurement, apoptosis assays in Jurkat and HSB2 cells","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis with knockdown studies, multiple inhibitor/siRNA approaches with defined molecular readout, single lab","pmids":["22787275"],"is_preprint":false},{"year":1998,"finding":"MRP1/ABCC1 gene expression is induced by pro-oxidants (tert-butylhydroquinone, DMNO, menadione) that increase intracellular reactive oxygen intermediates (ROI). Elevated intracellular GSH (via γ-GCSh overexpression) suppresses endogenous MRP1 and γ-GCSh expression by reducing ROI levels, indicating that intracellular ROI levels regulate MRP1 expression.","method":"Pro-oxidant treatment, flow cytometry (ROI measurement with dihydrorhodamine 123), stable γ-GCSh-transfected cell lines, Northern blot, GSH depletion experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable transfection epistasis combined with ROI measurement and GSH depletion, single lab, multiple methods","pmids":["9813007"],"is_preprint":false},{"year":2007,"finding":"Induction of ABCC1 by oxidative stress (tBHQ) is Nrf2-independent but Keap1-dependent: siRNA-mediated Nrf2 knockdown did not suppress tBHQ-induced ABCC1 mRNA elevation, whereas Keap1-specific siRNA knockdown increased ABCC1 mRNA. By contrast, ABCC2 and ABCG2 induction by tBHQ is Nrf2/Keap1-dependent.","method":"siRNA knockdown of Nrf2 and Keap1, real-time PCR for ABC transporter mRNA, tBHQ treatment in HepG2 cells, Nrf2 nuclear translocation assay","journal":"Journal of experimental therapeutics & oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA epistasis with two independent targets (Nrf2, Keap1) and defined mRNA readout, single lab","pmids":["18038766"],"is_preprint":false},{"year":2006,"finding":"MRP1/ABCC1 transporter activity is required for dendritic cell (DC) differentiation. Inhibition of MRP1 (but not P-glycoprotein) during in vitro DC differentiation impaired early DC development, resulting in morphological and phenotypic changes including maintained CD14 expression and decreased CD1a, CD1c, Langerin, CD40, CD86, and HLA-DR expression, and reduced ability to stimulate allogeneic T cells. Endogenous CD1 ligands sulfatide and GM1 were identified as MRP1 substrates, though exogenous addition did not restore DC differentiation.","method":"Specific MRP1 inhibitors during in vitro DC differentiation from monocytes, flow cytometry for surface markers, mixed lymphocyte reaction, substrate identification assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological loss-of-function with defined phenotypic and molecular readouts, identification of endogenous substrates, single lab","pmids":["16621983"],"is_preprint":false},{"year":2020,"finding":"EFHD2 promotes cisplatin resistance in NSCLC via the NOX4-ROS-ABCC1 axis: EFHD2 overexpression induces NOX4-mediated ROS production, which activates membrane expression of ABCC1 for drug efflux. EFHD2 knockdown reduced ABCC1 membrane expression and improved cisplatin sensitivity; ABCC1 knockdown phenocopied EFHD2 loss.","method":"EFHD2 overexpression and knockdown, NOX4 inhibition, ROS measurement, ABCC1 membrane expression by Western blot/flow cytometry, cisplatin resistance assays, murine xenograft model","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis with pathway placement (EFHD2→NOX4→ROS→ABCC1), multiple knockdown/overexpression approaches, in vivo validation, single lab","pmids":["32446175"],"is_preprint":false},{"year":2021,"finding":"ATF4 directly binds to the ABCC1 promoter region to activate its transcription in pancreatic cancer cells. TGF-β1 secreted by cancer-associated fibroblasts upregulates ATF4 via the SMAD2/3 pathway, which in turn transactivates ABCC1 to drive gemcitabine resistance.","method":"Chromatin immunoprecipitation (ChIP) of ATF4 at ABCC1 promoter, ATF4 silencing, TGF-β1 treatment, SMAD2/3 pathway analysis, gemcitabine resistance assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-confirmed direct promoter binding with pathway epistasis, single lab","pmids":["33782384"],"is_preprint":false},{"year":2022,"finding":"NRF2-dependent ABCC1 upregulation in glioblastoma promotes GSH depletion when system xc- is blocked (by Erastin), sensitizing cells to ferroptosis. ABCC1 silencing in T98G-shNRF2 cells reversed GSH depletion and conferred ferroptosis resistance while increasing TMZ sensitivity, establishing ABCC1 as a pro-ferroptotic NRF2 target responsible for collateral sensitivity.","method":"NRF2 and ABCC1 siRNA/shRNA silencing, ferroptosis inducers (Erastin, RSL3), Ferrostatin-1 rescue, GSH measurement, cell viability assays in U251MG and T98G glioblastoma cells","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic siRNA experiments with defined mechanistic readout (GSH levels, ferroptosis sensitivity), single lab","pmids":["35803910"],"is_preprint":false},{"year":2019,"finding":"A heterozygous missense variant in ABCC1 (p.Asn590Ser) causes nonsyndromic hearing loss. The variant results in altered subcellular distribution (cytomembrane and cytoplasm vs. cytomembrane only for wild-type), unstable mRNA, and decreased efflux capacity, establishing ABCC1 function in cochlea (stria vascularis and auditory nerve) as important for hearing.","method":"Genetic linkage analysis, exome sequencing, co-segregation analysis, immunofluorescence localization, real-time qPCR for mRNA stability, flow cytometry efflux assay, cochlear expression by in situ hybridization/immunostaining in mouse","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional validation methods for a disease-linked variant in a family study with cochlear expression data, single lab","pmids":["31273342"],"is_preprint":false},{"year":2010,"finding":"MRP1/ABCC1 plays a role in heavy metal detoxification in zebrafish. Overexpression of abcc1 improved survival of embryos exposed to Cd, Hg, and As, while overexpression of a transport-dead mutant (ABCC1-G1420D) sensitized embryos to toxic metals. abcc1 mRNA was induced by CdCl2, HgCl2, Pb(NO3)2, and arsenate in ZF4 cells and embryos.","method":"abcc1 overexpression and G1420D mutant expression in zebrafish embryos, heavy metal exposure survival assays, whole-mount in situ hybridization, real-time PCR","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function and loss-of-function (transport-dead mutant) in vivo with survival readout, single lab","pmids":["20842442"],"is_preprint":false},{"year":2020,"finding":"MRP1/ABCC1 mediates polarized apical-to-basolateral mercury export in placental epithelial cells, regulates intracellular GSH status, and protects placental cells from methyl mercury-induced oxidative stress, cytotoxicity, and apoptosis. siRNA-mediated MRP1 knockdown in HTR-8/SVneo cells caused mercury accumulation, reduced cell viability, increased apoptosis and oxidative stress.","method":"Transwell transport assays in MRP1-overexpressing MDCKII cells, siRNA knockdown in HTR-8/SVneo placental cells, mercury accumulation measurement, GSH status, cell viability, apoptosis and ROS assays, immunofluorescence localization in placental tissue","journal":"Archives of toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — polarized transport reconstitution plus siRNA knockdown with multiple cellular readouts, localization validation, single lab","pmids":["32915249"],"is_preprint":false},{"year":2018,"finding":"KDM5c (a histone demethylase) downregulates ABCC1 expression by demethylating H3K4me3 at the ABCC1 transcription start site (TSS). ChIP-qPCR confirmed that both H3K4me3 and KDM5c act on the same TSS region of the ABCC1 gene; KDM5c overexpression decreased ABCC1 mRNA/protein and reduced drug resistance, while KDM5c knockdown increased ABCC1 and drug resistance.","method":"KDM5c overexpression and siRNA knockdown, ChIP-qPCR for H3K4me3 and KDM5c at ABCC1 TSS, qPCR and Western blot for ABCC1, MTT drug resistance assay in HCT-8 and RKO colon cancer cells","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-confirmed epigenetic mechanism with gain/loss-of-function validation, single lab","pmids":["30257334"],"is_preprint":false},{"year":2009,"finding":"Chinese ABCC1 SNP Arg723Gln significantly reduces MRP1-mediated resistance to daunorubicin, doxorubicin, etoposide, vinblastine, and vincristine in HEK293 and CHO-K1 cells. Thr73Ile reduced resistance to methotrexate and etoposide; Arg1058Gln increased resistance to anthracyclines and etoposide. None of the variants affected MRP1 expression or trafficking.","method":"Site-directed mutagenesis recreating 4 SNPs, stable transfection in HEK293 and CHO-K1, immunoblotting, confocal microscopy, MTT drug resistance assay","journal":"Pharmacogenetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with functional drug resistance readouts in two cell lines, single lab","pmids":["19214144"],"is_preprint":false},{"year":2004,"finding":"Cellular folate status influences the transport activity of MRP1/ABCC1: folate-free conditions decreased MRP1-mediated daunorubicin efflux to 43% of normal, which was restored by leucovorin or folic acid repletion. This occurred without changes in MRP1 protein expression or cellular ATP/ADP pools, suggesting folate acts as a cofactor or allosteric modulator of MRP1 transport activity.","method":"MRP1-transfected ovarian carcinoma cells (2008/MRP1), folate deprivation/repletion, benzbromarone (MRP1-specific inhibitor) blockade, daunorubicin efflux assays","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection with specific MRP1 inhibitor and metabolic repletion, single lab","pmids":["15041471"],"is_preprint":false},{"year":2016,"finding":"As(GS)3 transport by MRP1/ABCC1 is modulated by N-linked glycosylation at Asn19/Asn23: glycosylation-deficient mutants display low Km (high affinity) similar to dephosphorylated wild-type, indicating that the default glycosylated form has lower affinity for As(GS)3. Cross-talk with phosphorylation at Tyr920/Ser921 controls transport kinetics.","method":"N-glycosylation site mutagenesis (N19Q/N23Q/N1006Q), membrane vesicle transport assays prepared with or without phosphatase inhibitors, in HEK293 and HeLa cells","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis of glycosylation and phosphorylation sites with in vitro kinetic transport assays, two-cell-line validation, phosphatase inhibitor controls (covered in same PMID 27297967 above)","pmids":["27297967"],"is_preprint":false},{"year":2019,"finding":"SOX2 transcriptionally upregulates ABCC1 to promote side population (SP) cell chemoresistance to paclitaxel in melanoma. SOX2 knockout depleted SP cells and reduced ABCC1 expression; SOX2 induction upregulated SP cells and ABCC1; ABCC1 knockout increased paclitaxel sensitivity. SOX2 was identified as a transcriptional activator of ABCC1.","method":"SOX2 knockout and inducible overexpression, ABCC1 knockout, side population assay (Hoechst 33342 exclusion), paclitaxel cytotoxicity assay, reporter assay for SOX2-ABCC1 transcription in melanoma cell lines","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout and overexpression epistasis with functional and molecular readouts, single lab","pmids":["31883360"],"is_preprint":false},{"year":2012,"finding":"ApoE/ApoE receptor-2/c-Jun N-terminal kinase (JNK) pathway regulates ABCC1 expression on cerebral microvessels. Methamphetamine reduced abluminal ABCC1 expression on cerebral microvessels; this was prevented by ApoE receptor-2 inhibition (receptor-associated protein) and inducible nitric oxide synthase inhibition (1400W), indicating ApoE signaling through ApoER2 deactivates JNK1/2 to regulate ABCC1.","method":"Methamphetamine treatment in C57BL/6J mice, ApoE receptor-2 inhibitor (RAP), iNOS inhibitor (1400W), Western blots of cerebral microvessel extracts, immunoprecipitation, immunohistochemistry","journal":"Stroke","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis in vivo with pathway placement (ApoE→ApoER2→JNK→ABCC1), single lab","pmids":["22426312"],"is_preprint":false},{"year":2020,"finding":"ABCC1 is a substrate transporter for COTI-2, a thiosemicarbazone anticancer compound, and confers resistance via efflux. ABCC1 recognition of COTI-2 requires formation of stable, non-reducible copper(II)-glutathione adducts; thiosemicarbazones forming reducible copper complexes with GSH are not ABCC1 substrates.","method":"Established COTI-2-resistant cell line (SW480/Coti) with confirmed ABCC1 overexpression, ABCC1 inhibitor reversal, copper complex synthesis and characterization, reduction kinetics with GSH, drug resistance assays","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identification with mechanistic explanation (copper-GSH adduct chemistry), inhibitor rescue, single lab","pmids":["33190481"],"is_preprint":false}],"current_model":"ABCC1/MRP1 is an ATP-driven plasma membrane efflux transporter with broad substrate specificity encompassing glutathione (GSH)/glucuronide/sulfate conjugates (including leukotriene C4, As(GS)3), the immunotransmitter cGAMP, sphingosine-1-phosphate, corticosterone, and various xenobiotics; its substrate recognition depends critically on specific transmembrane helices (TM6, 8, 10, 11, 14), cytoplasmic loop 5 and its interface with NBD2, and is modulated by N-linked glycosylation at Asn19/Asn23 and phosphorylation at Tyr920/Ser921; transcriptionally, ABCC1 is regulated by Notch1/CBF1, ATF4/SMAD2/3, SOX2, KDM5c-mediated H3K4me3 demethylation, and oxidative stress/ROI signaling; physiologically, ABCC1 controls STING-dependent innate immune signaling via cGAMP export, tissue-specific glucocorticoid availability (exporting corticosterone but not cortisol in adipose), dendritic cell differentiation, placental mercury detoxification, cochlear homeostasis, and cancer cell redox balance via GSH export."},"narrative":{"mechanistic_narrative":"ABCC1/MRP1 is an ATP-dependent plasma membrane efflux pump with broad substrate specificity that links cellular export of glutathione (GSH) conjugates and signaling lipids to innate immunity, redox homeostasis, hormone availability, and multidrug resistance [PMID:8663001, PMID:36070769]. Its prototypical substrate is the GSH conjugate leukotriene C4, and competitive-inhibition kinetics show that diverse compounds — glutathione-platinum complexes, anthracycline-GSH conjugates, and stable copper(II)-GSH thiosemicarbazone adducts — gain recognition at a shared substrate-binding site once conjugated to GSH [PMID:8663001, PMID:9647783, PMID:33190481]. The transporter also exports the STING agonist cGAMP, thereby limiting cell-intrinsic STING signaling and restraining cGAS-dependent autoimmunity [PMID:36070769], and exports sphingosine-1-phosphate to drive ERK signaling and a SphK1 feed-forward loop promoting breast tumor growth and metastasis [PMID:20110355, PMID:29523764]. Substrate handling is governed by specific transmembrane helices (TM6, 8, 10, 11, 14) and cytoplasmic-loop architecture: TM8/TM9 and Tyr440 are required for GSH-conjugate binding, cytoplasmic loop 5 and its interface with NBD2 (residues including Glu521/Glu535) are essential for interdomain folding, plasma-membrane expression, and catalysis, and N-glycosylation at Asn19/Asn23 together with phosphorylation at Tyr920/Ser921 reciprocally tune substrate affinity and transport capacity [PMID:14722114, PMID:18775981, PMID:21177244, PMID:22232552, PMID:27297967]. Physiologically, ABCC1 selectively exports corticosterone but not cortisol to control tissue glucocorticoid availability in adipose [PMID:27535620], detoxifies heavy metals including methylmercury and arsenic-GSH while protecting against oxidative stress [PMID:20842442, PMID:32915249], and is required for dendritic cell differentiation [PMID:16621983]. Transcriptionally it is activated by Notch1/CBF1, ATF4 downstream of TGF-β/SMAD2/3, SOX2, and NRF2/oxidative-stress signaling, and repressed by KDM5c-mediated H3K4me3 demethylation, coupling its expression to chemoresistance and ferroptosis sensitivity in multiple cancers [PMID:22143792, PMID:33782384, PMID:31883360, PMID:35803910, PMID:30257334]. A heterozygous p.Asn590Ser variant that mislocalizes the protein and reduces efflux causes nonsyndromic hearing loss [PMID:31273342].","teleology":[{"year":1996,"claim":"Established that MRP1 is an ATP-dependent GS-X pump exporting both a physiological GSH conjugate (LTC4) and a glutathione-drug complex through a shared binding site, defining its core transport mechanism and substrate logic.","evidence":"ATP-dependent transport and competitive inhibition kinetics in membrane vesicles from MRP1-overexpressing cells","pmids":["8663001"],"confidence":"High","gaps":["Did not resolve the structural identity of the shared binding site","Did not address GSH cotransport requirements for non-conjugated drugs"]},{"year":1998,"claim":"Extended the shared-binding-site model by showing anthracyclines become ABCC1 substrates only after glutathionation, explaining how broad chemoresistance arises from GSH conjugation.","evidence":"In vitro LTC4 transport competitive inhibition with chemically synthesized GS-anthracycline conjugates","pmids":["9647783"],"confidence":"High","gaps":["Whether conjugates are transported intact versus co-transported with GSH not directly shown"]},{"year":1998,"claim":"Showed ABCC1 expression is governed by intracellular redox state, linking the transporter to oxidative-stress adaptation rather than constitutive housekeeping.","evidence":"Pro-oxidant treatment and γ-GCSh overexpression with ROI and Northern-blot readouts","pmids":["9813007"],"confidence":"Medium","gaps":["Did not identify the transcription factors mediating ROI-driven induction","Single lab"]},{"year":2004,"claim":"Mapped specific transmembrane proline residues (TM6, 8, 10, 11, 14) and a cytoplasmic-loop proline as critical determinants of organic-anion transport and ATP dependence, beginning the structure-function dissection of substrate handling.","evidence":"Alanine-scanning mutagenesis with vesicular transport assays across multiple substrates","pmids":["14722114"],"confidence":"High","gaps":["No structural model of how these helices form the translocation pathway"]},{"year":2005,"claim":"Demonstrated that a natural coding SNP (Ala989Thr) lowers substrate affinity, providing pharmacogenetic evidence that ABCC1 sequence variation alters transport.","evidence":"Site-directed mutagenesis of 10 SNPs with vesicular transport assays in HEK cells","pmids":["16041243"],"confidence":"Medium","gaps":["Clinical consequence of the variant not established","Single lab"]},{"year":2006,"claim":"Revealed a developmental role beyond drug efflux: ABCC1 transport activity is required for dendritic cell differentiation, with endogenous CD1 ligands as candidate substrates.","evidence":"MRP1-specific pharmacological inhibition during in vitro DC differentiation with surface-marker and MLR readouts","pmids":["16621983"],"confidence":"Medium","gaps":["Exogenous substrate addition did not rescue differentiation, leaving the relevant transported molecule unconfirmed","Pharmacological rather than genetic loss-of-function"]},{"year":2008,"claim":"Localized GSH-conjugate binding to TM8/TM9 and cytoplasmic loops, identifying Tyr440 as a key residue whose mutation reduces LTC4 affinity and photolabeling.","evidence":"MRP1/MRP3 chimeras, point mutagenesis, and photoaffinity labeling with [3H]LTC4 and azido-GSH","pmids":["18775981"],"confidence":"High","gaps":["Did not resolve whether Tyr440 contacts GSH or the conjugated moiety"]},{"year":2010,"claim":"Identified S1P as an ABCC1 export substrate coupling the transporter to ERK signaling, expanding its role into lipid-mediated signal transduction.","evidence":"siRNA knockdown and inhibitor studies with S1P export and ERK phosphorylation in MCF-7 cells","pmids":["20110355"],"confidence":"Medium","gaps":["Direct ATP-dependent S1P transport not reconstituted","Single lab"]},{"year":2010,"claim":"Established cytoplasmic loop 5 and its NBD2 interface as essential for membrane expression and catalysis, distinguishing folding/trafficking determinants from the catalytic cycle.","evidence":"Site-directed mutagenesis with expression, azido-ATP trapping, and vesicular transport assays","pmids":["21177244"],"confidence":"High","gaps":["Structural basis of the CL5-NBD2 interface not defined"]},{"year":2010,"claim":"Demonstrated an in vivo metal-detoxification role using a transport-dead mutant, separating transport activity from mere expression.","evidence":"abcc1 and transport-dead G1420D overexpression in zebrafish embryos with heavy-metal survival assays","pmids":["20842442"],"confidence":"Medium","gaps":["Mammalian relevance not established in this study","Specific metal-GSH species transported not identified"]},{"year":2011,"claim":"Defined Notch1/CBF1 as a direct transcriptional activator of ABCC1, providing a signaling-to-expression axis underlying drug resistance.","evidence":"γ-secretase inhibition, shRNA, promoter-reporter, ChIP, EMSA, and CBF1-site mutagenesis","pmids":["22143792"],"confidence":"High","gaps":["Tissue contexts where Notch dominates ABCC1 regulation not delineated"]},{"year":2012,"claim":"Resolved differential folding requirements of CL5 glutamates, showing distinct conformational defects rescuable by chemical chaperone, refining the interdomain assembly model.","evidence":"Mutagenesis with proteasome/4-PBA rescue, conformational antibodies, and transport assays","pmids":["22232552"],"confidence":"High","gaps":["Atomic-level conformational changes inferred indirectly via antibody reactivity"]},{"year":2012,"claim":"Connected extracellular matrix signaling to ABCC1, showing collagen/β1-integrin-ERK signaling upregulates the transporter to confer doxorubicin resistance.","evidence":"Integrin/ERK inhibition and ABCC1 knockdown with intracellular drug and apoptosis readouts in leukemic T-cells","pmids":["22787275"],"confidence":"Medium","gaps":["Transcriptional effectors downstream of ERK not identified","Single lab"]},{"year":2016,"claim":"Established ABCC1 as a selective glucocorticoid exporter (corticosterone not cortisol), giving it a tissue-specific endocrine function in adipose.","evidence":"Probenecid inhibition and Abcc1 knockout mice with mass-spec steroid measurement and glucocorticoid-responsive gene expression","pmids":["27535620"],"confidence":"High","gaps":["Structural basis of corticosterone/cortisol discrimination not determined"]},{"year":2016,"claim":"Showed post-translational modifications (glycosylation at Asn19/23, phosphorylation at Tyr920/Ser921) reciprocally and epistatically tune substrate affinity and capacity, adding a regulatory layer to transport.","evidence":"Systematic PTM-site mutagenesis with As(GS)3 vesicular transport kinetics and phosphatase-inhibitor controls","pmids":["27297967"],"confidence":"High","gaps":["Kinases/phosphatases acting on Tyr920/Ser921 not identified","Generality across other substrates not tested"]},{"year":2020,"claim":"Identified ABCC1 as the effector of a EFHD2-NOX4-ROS axis controlling its membrane localization and cisplatin resistance, integrating redox signaling with transporter trafficking.","evidence":"EFHD2/ABCC1 overexpression and knockdown, NOX4 inhibition, ROS measurement, and xenografts","pmids":["32446175"],"confidence":"Medium","gaps":["Mechanism of ROS-driven membrane insertion not defined","Single lab"]},{"year":2020,"claim":"Showed ABCC1 mediates polarized placental mercury export and protects against methylmercury oxidative cytotoxicity, defining a barrier-detoxification role.","evidence":"Transwell transport in MDCKII cells, siRNA knockdown in placental cells, mercury/GSH/apoptosis readouts","pmids":["32915249"],"confidence":"Medium","gaps":["In vivo placental contribution not directly tested","Single lab"]},{"year":2020,"claim":"Clarified substrate-recognition chemistry by showing ABCC1 transports thiosemicarbazones only when they form stable non-reducible copper(II)-GSH adducts, refining the GSH-conjugate recognition rule.","evidence":"COTI-2-resistant ABCC1-overexpressing line, inhibitor reversal, and copper-GSH complex characterization","pmids":["33190481"],"confidence":"Medium","gaps":["Binding-site interactions with the copper adduct not mapped","Single lab"]},{"year":2021,"claim":"Added ATF4 (downstream of CAF-derived TGF-β1/SMAD2/3) as a direct transcriptional activator of ABCC1, linking the tumor microenvironment to gemcitabine resistance.","evidence":"ATF4 ChIP at ABCC1 promoter, ATF4 silencing, and TGF-β1/SMAD pathway analysis","pmids":["33782384"],"confidence":"Medium","gaps":["Relative contribution versus other activators not assessed","Single lab"]},{"year":2022,"claim":"Defined ABCC1 as the exporter limiting cell-intrinsic STING activation through cGAMP efflux, placing it as a regulator of innate immunity and autoimmunity.","evidence":"Reciprocal gain/loss-of-function cGAMP export assays and Trex1-/- mouse epistasis","pmids":["36070769"],"confidence":"High","gaps":["Whether cGAMP shares the GSH-conjugate binding site not addressed","Intercellular cGAMP transfer consequences not fully mapped"]},{"year":2022,"claim":"Showed NRF2-driven ABCC1 exports GSH to create collateral ferroptosis sensitivity in glioblastoma when system xc- is blocked, revealing a redox-balance role that can be therapeutically exploited.","evidence":"NRF2/ABCC1 silencing with Erastin/RSL3 ferroptosis induction, GSH measurement, and TMZ sensitivity in glioblastoma cells","pmids":["35803910"],"confidence":"Medium","gaps":["In vivo ferroptosis relevance not tested","Single lab"]},{"year":2018,"claim":"Identified KDM5c-mediated H3K4me3 demethylation at the ABCC1 TSS as an epigenetic repressor, complementing the transcription-factor regulation and linking chromatin state to chemoresistance.","evidence":"KDM5c overexpression/knockdown with ChIP-qPCR of H3K4me3 and KDM5c at the ABCC1 TSS and drug-resistance assays","pmids":["30257334"],"confidence":"Medium","gaps":["Upstream regulators of KDM5c recruitment unknown","Single lab"]},{"year":2019,"claim":"Provided direct disease evidence: a heterozygous p.Asn590Ser ABCC1 variant causing mislocalization and reduced efflux underlies nonsyndromic hearing loss, establishing cochlear ABCC1 function in hearing.","evidence":"Linkage/exome sequencing with co-segregation, localization, mRNA-stability, efflux assays, and cochlear expression mapping","pmids":["31273342"],"confidence":"Medium","gaps":["Mechanism by which efflux loss damages cochlea not defined","Single family/lab"]},{"year":null,"claim":"How the single broad substrate-binding pocket simultaneously accommodates GSH conjugates, cGAMP, S1P, and steroids, and how PTMs and trafficking signals are coordinated in vivo to dictate tissue-specific substrate preference, remains unresolved.","evidence":"No discovery in the timeline provides a unifying structural or in vivo integration model","pmids":[],"confidence":"Low","gaps":["No atomic-resolution structure of ABCC1 with diverse substrates in the corpus","Physiological hierarchy among competing substrates not established","Coupling between redox-driven trafficking and transcriptional/epigenetic regulation unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,2,11,23]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[1,4,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[8,18,21,23]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[1,11,22,23]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[21,25,30]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[15,20]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P33527","full_name":"Multidrug resistance-associated protein 1","aliases":["ATP-binding cassette sub-family C member 1","Glutathione-S-conjugate-translocating ATPase ABCC1","Leukotriene C(4) transporter","LTC4 transporter"],"length_aa":1531,"mass_kda":171.6,"function":"Mediates export of organic anions and drugs from the cytoplasm (PubMed:10064732, PubMed:11114332, PubMed:16230346, PubMed:7961706, PubMed:9281595). Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotrexate, antiviral drugs and other xenobiotics (PubMed:10064732, PubMed:11114332, PubMed:16230346, PubMed:7961706, PubMed:9281595). Confers resistance to anticancer drugs by decreasing accumulation of drug in cells, and by mediating ATP- and GSH-dependent drug export (PubMed:9281595). Hydrolyzes ATP with low efficiency (PubMed:16230346). Catalyzes the export of sphingosine 1-phosphate from mast cells independently of their degranulation (PubMed:17050692). Participates in inflammatory response by allowing export of leukotriene C4 from leukotriene C4-synthesizing cells (By similarity). Mediates ATP-dependent, GSH-independent cyclic GMP-AMP (cGAMP) export (PubMed:36070769). Thus, by limiting intracellular cGAMP concentrations negatively regulates the cGAS-STING pathway (PubMed:36070769). Exports S-geranylgeranyl-glutathione (GGG) in lymphoid cells and stromal compartments of lymphoid organs. ABCC1 (via extracellular transport) with GGT5 (via GGG catabolism) establish GGG gradients within lymphoid tissues to position P2RY8-positive lymphocytes at germinal centers in lymphoid follicles and restrict their chemotactic transmigration from blood vessels to the bone marrow parenchyma (By similarity). Mediates basolateral export of GSH-conjugated R- and S-prostaglandin A2 diastereomers in polarized epithelial cells (PubMed:9426231)","subcellular_location":"Cell membrane; Basolateral cell membrane","url":"https://www.uniprot.org/uniprotkb/P33527/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ABCC1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ALCAM","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ABCC1","total_profiled":1310},"omim":[{"mim_id":"618915","title":"DEAFNESS, AUTOSOMAL DOMINANT 77; DFNA77","url":"https://www.omim.org/entry/618915"},{"mim_id":"605251","title":"ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 5; ABCC5","url":"https://www.omim.org/entry/605251"},{"mim_id":"605250","title":"ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 4; ABCC4","url":"https://www.omim.org/entry/605250"},{"mim_id":"605088","title":"MAJOR VAULT PROTEIN; MVP","url":"https://www.omim.org/entry/605088"},{"mim_id":"604323","title":"ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 3; ABCC3","url":"https://www.omim.org/entry/604323"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ABCC1"},"hgnc":{"alias_symbol":["GS-X"],"prev_symbol":["MRP","MRP1"]},"alphafold":{"accession":"P33527","domains":[{"cath_id":"-","chopping":"19-199","consensus_level":"high","plddt":84.8916,"start":19,"end":199},{"cath_id":"3.40.50.300","chopping":"671-683_709-869","consensus_level":"medium","plddt":86.6485,"start":671,"end":869}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P33527","model_url":"https://alphafold.ebi.ac.uk/files/AF-P33527-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P33527-F1-predicted_aligned_error_v6.png","plddt_mean":82.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ABCC1","jax_strain_url":"https://www.jax.org/strain/search?query=ABCC1"},"sequence":{"accession":"P33527","fasta_url":"https://rest.uniprot.org/uniprotkb/P33527.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P33527/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P33527"}},"corpus_meta":[{"pmid":"15501592","id":"PMC_15501592","title":"Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1-ABCC6), in human brain.","date":"2004","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/15501592","citation_count":284,"is_preprint":false},{"pmid":"11557126","id":"PMC_11557126","title":"Toxicological relevance of the multidrug resistance protein 1, MRP1 (ABCC1) and related transporters.","date":"2001","source":"Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/11557126","citation_count":284,"is_preprint":false},{"pmid":"25281745","id":"PMC_25281745","title":"Multidrug resistance protein 1 (MRP1, ABCC1), a \"multitasking\" ATP-binding cassette (ABC) transporter.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25281745","citation_count":279,"is_preprint":false},{"pmid":"24050699","id":"PMC_24050699","title":"Targeting multidrug resistance protein 1 (MRP1, ABCC1): past, present, and future.","date":"2013","source":"Annual review of pharmacology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/24050699","citation_count":267,"is_preprint":false},{"pmid":"8663001","id":"PMC_8663001","title":"Coordinated induction of MRP/GS-X pump and gamma-glutamylcysteine synthetase by heavy metals in human leukemia cells.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8663001","citation_count":241,"is_preprint":false},{"pmid":"23723325","id":"PMC_23723325","title":"ABCC1, an ATP binding cassette protein from grape berry, transports anthocyanidin 3-O-Glucosides.","date":"2013","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/23723325","citation_count":222,"is_preprint":false},{"pmid":"16387301","id":"PMC_16387301","title":"Substrate recognition and transport by multidrug resistance protein 1 (ABCC1).","date":"2005","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/16387301","citation_count":217,"is_preprint":false},{"pmid":"20110355","id":"PMC_20110355","title":"Estradiol induces export of sphingosine 1-phosphate from breast cancer cells via ABCC1 and ABCG2.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20110355","citation_count":217,"is_preprint":false},{"pmid":"15012252","id":"PMC_15012252","title":"FROM VACUOLAR GS-X PUMPS TO MULTISPECIFIC ABC TRANSPORTERS.","date":"1998","source":"Annual review of plant physiology and plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15012252","citation_count":181,"is_preprint":false},{"pmid":"18085475","id":"PMC_18085475","title":"Role of the MRP1/ABCC1 multidrug transporter protein in cancer.","date":"2007","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/18085475","citation_count":173,"is_preprint":false},{"pmid":"16960658","id":"PMC_16960658","title":"Modulation of function of three ABC drug transporters, P-glycoprotein (ABCB1), mitoxantrone resistance protein (ABCG2) and multidrug resistance protein 1 (ABCC1) by tetrahydrocurcumin, a major metabolite of curcumin.","date":"2006","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16960658","citation_count":170,"is_preprint":false},{"pmid":"19165709","id":"PMC_19165709","title":"ABC transporter (P-gp/ABCB1, MRP1/ABCC1, BCRP/ABCG2) expression in the developing human CNS.","date":"2009","source":"Neuropediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/19165709","citation_count":146,"is_preprint":false},{"pmid":"9813007","id":"PMC_9813007","title":"Expression of multidrug resistance protein/GS-X pump and gamma-glutamylcysteine synthetase genes is regulated by oxidative stress.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9813007","citation_count":143,"is_preprint":false},{"pmid":"29602203","id":"PMC_29602203","title":"LncRNA NR2F1-AS1 regulates hepatocellular carcinoma oxaliplatin resistance by targeting ABCC1 via miR-363.","date":"2018","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29602203","citation_count":138,"is_preprint":false},{"pmid":"17187268","id":"PMC_17187268","title":"Portrait of multifaceted transporter, the multidrug resistance-associated protein 1 (MRP1/ABCC1).","date":"2006","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/17187268","citation_count":134,"is_preprint":false},{"pmid":"18680196","id":"PMC_18680196","title":"Differential expression of the multidrug resistance-related proteins ABCb1 and ABCc1 between blood-brain interfaces.","date":"2008","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/18680196","citation_count":119,"is_preprint":false},{"pmid":"36070769","id":"PMC_36070769","title":"ABCC1 transporter exports the immunostimulatory cyclic dinucleotide cGAMP.","date":"2022","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/36070769","citation_count":115,"is_preprint":false},{"pmid":"21143116","id":"PMC_21143116","title":"Structural and functional properties of human multidrug resistance protein 1 (MRP1/ABCC1).","date":"2011","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21143116","citation_count":109,"is_preprint":false},{"pmid":"17172311","id":"PMC_17172311","title":"Inhibition of MRP1/ABCC1, MRP2/ABCC2, and MRP3/ABCC3 by nucleoside, nucleotide, and non-nucleoside reverse transcriptase inhibitors.","date":"2006","source":"Drug metabolism and disposition: the biological fate of chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/17172311","citation_count":109,"is_preprint":false},{"pmid":"22143792","id":"PMC_22143792","title":"Notch1 regulates the expression of the multidrug resistance gene ABCC1/MRP1 in cultured cancer cells.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22143792","citation_count":92,"is_preprint":false},{"pmid":"31960989","id":"PMC_31960989","title":"Exosomes from CD133+ cells carrying circ-ABCC1 mediate cell stemness and metastasis in colorectal cancer.","date":"2020","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31960989","citation_count":86,"is_preprint":false},{"pmid":"31986409","id":"PMC_31986409","title":"CircPVT1 contributes to chemotherapy resistance of lung adenocarcinoma through miR-145-5p/ABCC1 axis.","date":"2020","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/31986409","citation_count":86,"is_preprint":false},{"pmid":"29069754","id":"PMC_29069754","title":"LncRNA FENDRR sensitizes doxorubicin-resistance of osteosarcoma cells through down-regulating ABCB1 and ABCC1.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29069754","citation_count":84,"is_preprint":false},{"pmid":"35803910","id":"PMC_35803910","title":"High levels of NRF2 sensitize temozolomide-resistant glioblastoma cells to ferroptosis via ABCC1/MRP1 upregulation.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35803910","citation_count":81,"is_preprint":false},{"pmid":"18038766","id":"PMC_18038766","title":"Nrf2-dependent and -independent induction of ABC transporters ABCC1, ABCC2, and ABCG2 in HepG2 cells under oxidative stress.","date":"2007","source":"Journal of experimental therapeutics & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/18038766","citation_count":80,"is_preprint":false},{"pmid":"19390592","id":"PMC_19390592","title":"Vandetanib (Zactima, ZD6474) antagonizes ABCC1- and ABCG2-mediated multidrug resistance by inhibition of their transport function.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19390592","citation_count":78,"is_preprint":false},{"pmid":"16006996","id":"PMC_16006996","title":"Polymorphisms of MRP1 (ABCC1) and related ATP-dependent drug transporters.","date":"2005","source":"Pharmacogenetics and genomics","url":"https://pubmed.ncbi.nlm.nih.gov/16006996","citation_count":73,"is_preprint":false},{"pmid":"33782384","id":"PMC_33782384","title":"Cancer-associated fibroblasts-mediated ATF4 expression promotes malignancy and gemcitabine resistance in pancreatic cancer via the TGF-β1/SMAD2/3 pathway and ABCC1 transactivation.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33782384","citation_count":72,"is_preprint":false},{"pmid":"15328029","id":"PMC_15328029","title":"Expression of P-glycoprotein (ABCB1) and Mrp1 (ABCC1) in adult rat brain: focus on astrocytes.","date":"2004","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/15328029","citation_count":70,"is_preprint":false},{"pmid":"29966655","id":"PMC_29966655","title":"Long non-coding RNA KCNQ1OT1 modulates oxaliplatin resistance in hepatocellular carcinoma through miR-7-5p/ ABCC1 axis.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29966655","citation_count":70,"is_preprint":false},{"pmid":"19552816","id":"PMC_19552816","title":"Expression of multidrug resistance markers ABCB1 (MDR-1/P-gp) and ABCC1 (MRP-1) in renal cell carcinoma.","date":"2009","source":"BMC urology","url":"https://pubmed.ncbi.nlm.nih.gov/19552816","citation_count":69,"is_preprint":false},{"pmid":"26108539","id":"PMC_26108539","title":"miR-7 modulates chemoresistance of small cell lung cancer by repressing MRP1/ABCC1.","date":"2015","source":"International journal of experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26108539","citation_count":69,"is_preprint":false},{"pmid":"18464048","id":"PMC_18464048","title":"Pharmacogenomics of MRP transporters (ABCC1-5) and BCRP (ABCG2).","date":"2008","source":"Drug metabolism reviews","url":"https://pubmed.ncbi.nlm.nih.gov/18464048","citation_count":68,"is_preprint":false},{"pmid":"16041243","id":"PMC_16041243","title":"Functional characterization of non-synonymous single nucleotide polymorphisms in the gene encoding human multidrug resistance protein 1 (MRP1/ABCC1).","date":"2005","source":"Pharmacogenetics and genomics","url":"https://pubmed.ncbi.nlm.nih.gov/16041243","citation_count":68,"is_preprint":false},{"pmid":"19768722","id":"PMC_19768722","title":"Combined pharmacophore modeling, docking, and 3D QSAR studies of ABCB1 and ABCC1 transporter inhibitors.","date":"2009","source":"ChemMedChem","url":"https://pubmed.ncbi.nlm.nih.gov/19768722","citation_count":67,"is_preprint":false},{"pmid":"9647783","id":"PMC_9647783","title":"Doxorubicin- and daunorubicin-glutathione conjugates, but not unconjugated drugs, competitively inhibit leukotriene C4 transport mediated by MRP/GS-X pump.","date":"1998","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9647783","citation_count":65,"is_preprint":false},{"pmid":"29523764","id":"PMC_29523764","title":"ABCC1-Exported Sphingosine-1-phosphate, Produced by Sphingosine Kinase 1, Shortens Survival of Mice and Patients with Breast Cancer.","date":"2018","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/29523764","citation_count":62,"is_preprint":false},{"pmid":"33459081","id":"PMC_33459081","title":"ABCB1, ABCG2, ABCC1, ABCC2, and ABCC3 drug transporter polymorphisms and their impact on drug bioavailability: what is our current understanding?","date":"2021","source":"Expert opinion on drug metabolism & toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/33459081","citation_count":59,"is_preprint":false},{"pmid":"20842442","id":"PMC_20842442","title":"Molecular analysis and heavy metal detoxification of ABCC1/MRP1 in zebrafish.","date":"2010","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/20842442","citation_count":58,"is_preprint":false},{"pmid":"19214144","id":"PMC_19214144","title":"Characterization and analyses of multidrug resistance-associated protein 1 (MRP1/ABCC1) polymorphisms in Chinese population.","date":"2009","source":"Pharmacogenetics and genomics","url":"https://pubmed.ncbi.nlm.nih.gov/19214144","citation_count":58,"is_preprint":false},{"pmid":"16868918","id":"PMC_16868918","title":"MRP1/GS-X pump ATPase expression: is this the explanation for the cytoprotection of the heart against oxidative stress-induced redox imbalance in comparison to skeletal muscle cells?","date":"2007","source":"Cell biochemistry and function","url":"https://pubmed.ncbi.nlm.nih.gov/16868918","citation_count":57,"is_preprint":false},{"pmid":"14722114","id":"PMC_14722114","title":"Identification of proline residues in the core cytoplasmic and transmembrane regions of multidrug resistance protein 1 (MRP1/ABCC1) important for transport function, substrate specificity, and nucleotide interactions.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14722114","citation_count":56,"is_preprint":false},{"pmid":"29876787","id":"PMC_29876787","title":"miR-1268a regulates ABCC1 expression to mediate temozolomide resistance in glioblastoma.","date":"2018","source":"Journal of neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29876787","citation_count":55,"is_preprint":false},{"pmid":"23396606","id":"PMC_23396606","title":"Genetic variability in the multidrug resistance associated protein-1 (ABCC1/MRP1) predicts hematological toxicity in breast cancer patients receiving (neo-)adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC).","date":"2013","source":"Annals of oncology : official journal of the European Society for Medical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/23396606","citation_count":55,"is_preprint":false},{"pmid":"23470221","id":"PMC_23470221","title":"Fluorescent substrates for flow cytometric evaluation of efflux inhibition in ABCB1, ABCC1, and ABCG2 transporters.","date":"2013","source":"Analytical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23470221","citation_count":54,"is_preprint":false},{"pmid":"16621983","id":"PMC_16621983","title":"Dendritic cells require multidrug resistance protein 1 (ABCC1) transporter activity for differentiation.","date":"2006","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16621983","citation_count":53,"is_preprint":false},{"pmid":"22787275","id":"PMC_22787275","title":"Collagen/β1 integrin signaling up-regulates the ABCC1/MRP-1 transporter in an ERK/MAPK-dependent manner.","date":"2012","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/22787275","citation_count":52,"is_preprint":false},{"pmid":"25714665","id":"PMC_25714665","title":"Involvement of miR-133a and miR-326 in ADM resistance of HepG2 through modulating expression of ABCC1.","date":"2015","source":"Journal of drug targeting","url":"https://pubmed.ncbi.nlm.nih.gov/25714665","citation_count":50,"is_preprint":false},{"pmid":"33190481","id":"PMC_33190481","title":"Cancer Cell Resistance Against the Clinically Investigated Thiosemicarbazone COTI-2 Is Based on Formation of Intracellular Copper Complex Glutathione Adducts and ABCC1-Mediated Efflux.","date":"2020","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33190481","citation_count":50,"is_preprint":false},{"pmid":"24782036","id":"PMC_24782036","title":"NOTCH1 signaling promotes chemoresistance via regulating ABCC1 expression in prostate cancer stem cells.","date":"2014","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24782036","citation_count":49,"is_preprint":false},{"pmid":"26548759","id":"PMC_26548759","title":"Targeting ABCB1 and ABCC1 with their Specific Inhibitor CBT-1® can Overcome Drug Resistance in Osteosarcoma.","date":"2016","source":"Current cancer drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/26548759","citation_count":49,"is_preprint":false},{"pmid":"33420675","id":"PMC_33420675","title":"Friend or foe: ABCG2, ABCC1 and ABCB1 expression in triple-negative breast cancer.","date":"2021","source":"Breast cancer (Tokyo, Japan)","url":"https://pubmed.ncbi.nlm.nih.gov/33420675","citation_count":48,"is_preprint":false},{"pmid":"32446175","id":"PMC_32446175","title":"EFHD2 contributes to non-small cell lung cancer cisplatin resistance by the activation of NOX4-ROS-ABCC1 axis.","date":"2020","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/32446175","citation_count":48,"is_preprint":false},{"pmid":"21297965","id":"PMC_21297965","title":"Modulation of Mrp1 (ABCc1) and Pgp (ABCb1) by bilirubin at the blood-CSF and blood-brain barriers in the Gunn rat.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21297965","citation_count":48,"is_preprint":false},{"pmid":"27535620","id":"PMC_27535620","title":"ABCC1 confers tissue-specific sensitivity to cortisol versus corticosterone: A rationale for safer glucocorticoid replacement therapy.","date":"2016","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27535620","citation_count":48,"is_preprint":false},{"pmid":"33570734","id":"PMC_33570734","title":"Exosomal circ_PIP5K1A regulates the progression of non-small cell lung cancer and cisplatin sensitivity by miR-101/ABCC1 axis.","date":"2021","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33570734","citation_count":47,"is_preprint":false},{"pmid":"22086004","id":"PMC_22086004","title":"Multidrug resistance-associated protein 1 (MRP1/ABCC1) polymorphism: from discovery to clinical application.","date":"2011","source":"Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/22086004","citation_count":46,"is_preprint":false},{"pmid":"24024181","id":"PMC_24024181","title":"Clinicopathological impact of ABCC1/MRP1 and ABCC4/MRP4 in epithelial ovarian carcinoma.","date":"2013","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/24024181","citation_count":45,"is_preprint":false},{"pmid":"25218792","id":"PMC_25218792","title":"Vascular and extravascular distribution of the ATP-binding cassette transporters ABCB1 and ABCC1 in aged human brain and pituitary.","date":"2014","source":"Mechanisms of ageing and development","url":"https://pubmed.ncbi.nlm.nih.gov/25218792","citation_count":45,"is_preprint":false},{"pmid":"26943020","id":"PMC_26943020","title":"Pyrrolopyrimidine Derivatives as Novel Inhibitors of Multidrug Resistance-Associated Protein 1 (MRP1, ABCC1).","date":"2016","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26943020","citation_count":41,"is_preprint":false},{"pmid":"18775981","id":"PMC_18775981","title":"Structural determinants of substrate specificity differences between human multidrug resistance protein (MRP) 1 (ABCC1) and MRP3 (ABCC3).","date":"2008","source":"Drug metabolism and disposition: the biological fate of chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/18775981","citation_count":40,"is_preprint":false},{"pmid":"30279206","id":"PMC_30279206","title":"ANRIL promotes chemoresistance via disturbing expression of ABCC1 by regulating the expression of Let-7a in colorectal cancer.","date":"2018","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/30279206","citation_count":37,"is_preprint":false},{"pmid":"18633430","id":"PMC_18633430","title":"A novel arsenical has antitumor activity toward As2O3-resistant and MRP1/ABCC1-overexpressing cell lines.","date":"2008","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/18633430","citation_count":36,"is_preprint":false},{"pmid":"27689338","id":"PMC_27689338","title":"Promoter methylation patterns of ABCB1, ABCC1 and ABCG2 in human cancer cell lines, multidrug-resistant cell models and tumor, tumor-adjacent and tumor-distant tissues from breast cancer patients.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27689338","citation_count":35,"is_preprint":false},{"pmid":"34339285","id":"PMC_34339285","title":"Circular RNAcirc_0076305 Promotes Cisplatin (DDP) Resistance of Non-Small Cell Lung Cancer Cells by Regulating ABCC1 Through miR-186-5p.","date":"2021","source":"Cancer biotherapy & radiopharmaceuticals","url":"https://pubmed.ncbi.nlm.nih.gov/34339285","citation_count":34,"is_preprint":false},{"pmid":"15041471","id":"PMC_15041471","title":"Folate concentration dependent transport activity of the Multidrug Resistance Protein 1 (ABCC1).","date":"2004","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15041471","citation_count":34,"is_preprint":false},{"pmid":"30257334","id":"PMC_30257334","title":"KDM5c inhibits multidrug resistance of colon cancer cell line by down-regulating ABCC1.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/30257334","citation_count":33,"is_preprint":false},{"pmid":"32916774","id":"PMC_32916774","title":"LINC00470 promotes tumour proliferation and invasion, and attenuates chemosensitivity through the LINC00470/miR-134/Myc/ABCC1 axis in glioma.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32916774","citation_count":32,"is_preprint":false},{"pmid":"22098604","id":"PMC_22098604","title":"Variation and evolution of the ABC transporter genes ABCB1, ABCC1, ABCG2, ABCG5 and ABCG8: implication for pharmacogenetics and disease.","date":"2011","source":"Drug metabolism and drug interactions","url":"https://pubmed.ncbi.nlm.nih.gov/22098604","citation_count":32,"is_preprint":false},{"pmid":"30941807","id":"PMC_30941807","title":"The A-B-C of small-molecule ABC transport protein modulators: From inhibition to activation-a case study of multidrug resistance-associated protein 1 (ABCC1).","date":"2019","source":"Medicinal research reviews","url":"https://pubmed.ncbi.nlm.nih.gov/30941807","citation_count":32,"is_preprint":false},{"pmid":"18851956","id":"PMC_18851956","title":"ABCB1 and ABCC1 expression in peripheral mononuclear cells is influenced by gene polymorphisms and atorvastatin treatment.","date":"2008","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18851956","citation_count":32,"is_preprint":false},{"pmid":"34659894","id":"PMC_34659894","title":"Sphingosine 1-phosphate (S1P) produced by sphingosine kinase 1 (SphK1) and exported via ABCC1 is related to hepatocellular carcinoma (HCC) progression.","date":"2021","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/34659894","citation_count":32,"is_preprint":false},{"pmid":"29445446","id":"PMC_29445446","title":"Down-regulation of miR-210-3p encourages chemotherapy resistance of renal cell carcinoma via modulating ABCC1.","date":"2018","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/29445446","citation_count":32,"is_preprint":false},{"pmid":"35203285","id":"PMC_35203285","title":"Upregulation of USP22 and ABCC1 during Sorafenib Treatment of Hepatocellular Carcinoma Contribute to Development of Resistance.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35203285","citation_count":30,"is_preprint":false},{"pmid":"26774038","id":"PMC_26774038","title":"Flavonoid derivatives as selective ABCC1 modulators: Synthesis and functional characterization.","date":"2015","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26774038","citation_count":30,"is_preprint":false},{"pmid":"21177244","id":"PMC_21177244","title":"Expression and function of human MRP1 (ABCC1) is dependent on amino acids in cytoplasmic loop 5 and its interface with nucleotide binding domain 2.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21177244","citation_count":30,"is_preprint":false},{"pmid":"22232552","id":"PMC_22232552","title":"Mutation of Glu521 or Glu535 in cytoplasmic loop 5 causes differential misfolding in multiple domains of multidrug and organic anion transporter MRP1 (ABCC1).","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22232552","citation_count":28,"is_preprint":false},{"pmid":"33081264","id":"PMC_33081264","title":"Roles of ABCC1 and ABCC4 in Proliferation and Migration of Breast Cancer Cell Lines.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33081264","citation_count":27,"is_preprint":false},{"pmid":"26300056","id":"PMC_26300056","title":"Dinaciclib, a cyclin-dependent kinase inhibitor, is a substrate of human ABCB1 and ABCG2 and an inhibitor of human ABCC1 in vitro.","date":"2015","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26300056","citation_count":27,"is_preprint":false},{"pmid":"33493421","id":"PMC_33493421","title":"Ursolic Acid Enhances Cytotoxicity of Doxorubicin-Resistant Triple-Negative Breast Cancer Cells via ZEB1-AS1/miR-186-5p/ABCC1 Axis.","date":"2021","source":"Cancer biotherapy & radiopharmaceuticals","url":"https://pubmed.ncbi.nlm.nih.gov/33493421","citation_count":27,"is_preprint":false},{"pmid":"22871336","id":"PMC_22871336","title":"Detection of ABCC1 expression in classical Hodgkin lymphoma is associated with increased risk of treatment failure using standard chemotherapy protocols.","date":"2012","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/22871336","citation_count":27,"is_preprint":false},{"pmid":"27110952","id":"PMC_27110952","title":"MOLECULAR CLONING, EXPRESSION PATTERN OF MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 1 (MRP1, ABCC1) GENE, AND THE SYNERGISTIC EFFECTS OF VERAPAMIL ON TOXICITY OF TWO INSECTICIDES IN THE BIRD CHERRY-OAT APHID.","date":"2016","source":"Archives of insect biochemistry and physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27110952","citation_count":27,"is_preprint":false},{"pmid":"35324517","id":"PMC_35324517","title":"LncRNA SNHG11 enhances bevacizumab resistance in colorectal cancer by mediating miR-1207-5p/ABCC1 axis.","date":"2022","source":"Anti-cancer drugs","url":"https://pubmed.ncbi.nlm.nih.gov/35324517","citation_count":26,"is_preprint":false},{"pmid":"33718236","id":"PMC_33718236","title":"Overexpression of ABCC1 Confers Drug Resistance to Betulin.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33718236","citation_count":26,"is_preprint":false},{"pmid":"24231527","id":"PMC_24231527","title":"Jadomycins are cytotoxic to ABCB1-, ABCC1-, and ABCG2-overexpressing MCF7 breast cancer cells.","date":"2014","source":"Anti-cancer drugs","url":"https://pubmed.ncbi.nlm.nih.gov/24231527","citation_count":26,"is_preprint":false},{"pmid":"38340425","id":"PMC_38340425","title":"Overexpression of ABCC1 and ABCG2 confers resistance to talazoparib, a poly (ADP-Ribose) polymerase inhibitor.","date":"2023","source":"Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/38340425","citation_count":25,"is_preprint":false},{"pmid":"25986678","id":"PMC_25986678","title":"Interactions of cyclin-dependent kinase inhibitors AT-7519, flavopiridol and SNS-032 with ABCB1, ABCG2 and ABCC1 transporters and their potential to overcome multidrug resistance in vitro.","date":"2015","source":"Cancer chemotherapy and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25986678","citation_count":25,"is_preprint":false},{"pmid":"28881788","id":"PMC_28881788","title":"miR-133b down-regulates ABCC1 and enhances the sensitivity of CRC to anti-tumor drugs.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28881788","citation_count":24,"is_preprint":false},{"pmid":"11543717","id":"PMC_11543717","title":"Antiproliferative prostaglandins and the MRP/GS-X pump role in cancer immunosuppression and insight into new strategies in cancer gene therapy.","date":"2001","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/11543717","citation_count":24,"is_preprint":false},{"pmid":"11139250","id":"PMC_11139250","title":"Identification of novel polymorphisms in the pM5 and MRP1 (ABCC1) genes at locus 16p13.1 and exclusion of both genes as responsible for pseudoxanthoma elasticum.","date":"2001","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/11139250","citation_count":24,"is_preprint":false},{"pmid":"32787102","id":"PMC_32787102","title":"Superior Pyrimidine Derivatives as Selective ABCG2 Inhibitors and Broad-Spectrum ABCB1, ABCC1, and ABCG2 Antagonists.","date":"2020","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32787102","citation_count":23,"is_preprint":false},{"pmid":"35510797","id":"PMC_35510797","title":"Sec24C mediates a Golgi-independent trafficking pathway that is required for tonoplast localisation of ABCC1 and ABCC2.","date":"2022","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/35510797","citation_count":23,"is_preprint":false},{"pmid":"32915249","id":"PMC_32915249","title":"In vitro function and in situ localization of Multidrug Resistance-associated Protein (MRP)1 (ABCC1) suggest a protective role against methyl mercury-induced oxidative stress in the human placenta.","date":"2020","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/32915249","citation_count":23,"is_preprint":false},{"pmid":"31273342","id":"PMC_31273342","title":"Extrusion pump ABCC1 was first linked with nonsyndromic hearing loss in humans by stepwise genetic analysis.","date":"2019","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31273342","citation_count":22,"is_preprint":false},{"pmid":"27810353","id":"PMC_27810353","title":"Pyrrolopyrimidine derivatives and purine analogs as novel activators of Multidrug Resistance-associated Protein 1 (MRP1, ABCC1).","date":"2016","source":"Biochimica et biophysica acta. Biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/27810353","citation_count":22,"is_preprint":false},{"pmid":"24080162","id":"PMC_24080162","title":"Two polymorphic variants of ABCC1 selectively alter drug resistance and inhibitor sensitivity of the multidrug and organic anion transporter multidrug resistance protein 1.","date":"2013","source":"Drug metabolism and disposition: the biological fate of chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/24080162","citation_count":22,"is_preprint":false},{"pmid":"29971014","id":"PMC_29971014","title":"Specific Binding Protein ABCC1 Is Associated With Cry2Ab Toxicity in Helicoverpa armigera.","date":"2018","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29971014","citation_count":22,"is_preprint":false},{"pmid":"22426312","id":"PMC_22426312","title":"Apolipoprotein-E controls adenosine triphosphate-binding cassette transporters ABCB1 and ABCC1 on cerebral microvessels after methamphetamine intoxication.","date":"2012","source":"Stroke","url":"https://pubmed.ncbi.nlm.nih.gov/22426312","citation_count":22,"is_preprint":false},{"pmid":"31883360","id":"PMC_31883360","title":"SOX2 upregulates side population cells and enhances their chemoresistant ability by transactivating ABCC1 expression contributing to intrinsic resistance to paclitaxel in melanoma.","date":"2019","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/31883360","citation_count":21,"is_preprint":false},{"pmid":"27297967","id":"PMC_27297967","title":"Arsenic Triglutathione [As(GS)3] Transport by Multidrug Resistance Protein 1 (MRP1/ABCC1) Is Selectively Modified by Phosphorylation of Tyr920/Ser921 and Glycosylation of Asn19/Asn23.","date":"2016","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/27297967","citation_count":21,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55948,"output_tokens":9040,"usd":0.151722,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18933,"output_tokens":6291,"usd":0.12597,"stage2_stop_reason":"end_turn"},"total_usd":0.277692,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"ABCC1 directly exports cyclic GMP-AMP (cGAMP) in an ATP-dependent manner. ABCC1 overexpression enhanced cGAMP export and limited STING signaling, while ABCC1 loss reduced cGAMP export and potentiated STING signaling. ABCC1 deficiency exacerbated cGAS-dependent autoimmunity in Trex1-/- mice, establishing ABCC1-mediated cGAMP export as a key regulatory mechanism limiting cell-intrinsic STING activation.\",\n      \"method\": \"Overexpression and loss-of-function studies in mouse and human cells, cGAMP export assays, Trex1-/- mouse model epistasis\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function with defined molecular phenotype (cGAMP export, STING signaling), replicated in mouse model with autoimmune disease endpoint\",\n      \"pmids\": [\"36070769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"MRP1/ABCC1 (GS-X pump) transports both leukotriene C4 (LTC4) and the glutathione-platinum complex (GS-Pt) in an ATP-dependent manner. Glutathione-platinum complex, but not cisplatin itself, competitively inhibited ATP-dependent LTC4 transport in membrane vesicles from MRP1-overexpressing cells, indicating a shared binding site.\",\n      \"method\": \"ATP-dependent transport assays in plasma membrane vesicles from MRP1-overexpressing cells; competitive inhibition kinetics\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro transport reconstitution in membrane vesicles with competitive inhibition kinetics; replicated across multiple labs subsequently\",\n      \"pmids\": [\"8663001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ABCC1 exports sphingosine 1-phosphate (S1P) and dihydro-S1P from breast cancer cells. Estradiol-induced S1P export required estrogen receptor-alpha and was suppressed by pharmacological inhibitors or siRNA knockdown of ABCC1. This ABCC1-mediated S1P export activated ERK1/2 signaling downstream.\",\n      \"method\": \"Pharmacological inhibition and siRNA knockdown of ABCC1, S1P export measurement, ERK1/2 phosphorylation assays in MCF-7 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown and inhibitor studies with defined molecular readout (S1P export, ERK activation), single lab\",\n      \"pmids\": [\"20110355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ABCC1-exported S1P (produced by SphK1) promotes breast cancer tumor growth, angiogenesis, lymphangiogenesis, metastasis, and upregulates SphK1 transcription in a feed-forward manner. Overexpression of ABCC1 (but not ABCB1) in breast cancer cells enhanced S1P secretion, proliferation, migration, and tumor growth in mouse mammary fat pad implantation models.\",\n      \"method\": \"ABCC1 overexpression in MCF-7 and 4T1 cells, in vivo mammary fat pad tumor implantation, S1P secretion measurement\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro gain-of-function with defined molecular and phenotypic readouts, single lab\",\n      \"pmids\": [\"29523764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Doxorubicin- and daunorubicin-glutathione conjugates (but not unconjugated drugs) competitively inhibit LTC4 transport by MRP1/GS-X pump, with Ki values of 60–200 nM, indicating that glutathionation enables anthracycline recognition at the shared substrate-binding site of ABCC1.\",\n      \"method\": \"In vitro LTC4 transport assay using MRP1-overexpressing membrane vesicles; competitive inhibition kinetics with synthesized GS-conjugates\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with competitive inhibition kinetics, chemically defined substrates, replicated concept\",\n      \"pmids\": [\"9647783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Notch1 intracellular domain (N1IC) transcriptionally upregulates ABCC1/MRP1 expression via the transcription factor CBF1 binding to specific sites in the ABCC1 promoter. Reducing N1IC (by γ-secretase inhibitor or shRNA) decreased ABCC1 expression; ectopic N1IC increased ABCC1 and drug resistance. ChIP and gel-shift assays confirmed N1IC-activated CBF1 interaction with the ABCC1 promoter; mutation of CBF1 binding sites attenuated promoter activity.\",\n      \"method\": \"γ-secretase inhibitor and shRNA knockdown, ectopic overexpression, ABCC1 promoter-reporter assay, ChIP, gel-shift (EMSA), site-directed mutagenesis of CBF1 binding sites\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, EMSA, promoter mutagenesis, genetic knockdown/overexpression) in one study\",\n      \"pmids\": [\"22143792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NOTCH1 intracellular domain (ICN1) directly binds to the promoter region of ABCC1 to transactivate its expression in prostate cancer stem cells, resulting in enhanced chemoresistance. ChIP-PCR confirmed ICN1 occupancy at the ABCC1 promoter; shRNA knockdown of NOTCH1 decreased ABCC1 expression and improved chemosensitivity.\",\n      \"method\": \"ChIP-PCR, shRNA knockdown, quantitative RT-PCR, Western blot, MTT chemosensitivity assay\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-PCR and knockdown with functional readout, single lab\",\n      \"pmids\": [\"24782036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Proline residues in transmembrane helices 6, 8, 10, 11 (MSD2) and 14 (MSD3) of MRP1/ABCC1 are critical for organic anion transport function. Ala substitution of TM6-Pro343, TM8-Pro448, TM10-Pro557, TM11-Pro595, and TM14-Pro1088 significantly reduced transport of five organic anion substrates. Pro1150 in cytoplasmic loop 7 (CL7) differentially modulates substrate-specific transport and ATP dependence.\",\n      \"method\": \"Alanine-scanning mutagenesis of 18 Pro residues; vesicular transport assays for multiple organic anion substrates; ATP binding studies in HEK cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis combined with in vitro transport reconstitution across multiple substrates in one study\",\n      \"pmids\": [\"14722114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cytoplasmic loop 5 (CL5) of MRP1/ABCC1 is critical for plasma membrane expression and transport function. Ala substitution of conserved charged residues Lys513, Lys516, Glu521, and Glu535 markedly reduced MRP1 protein levels; NBD2 residues His1364 and Arg1367 at the CL5 interface also reduced MRP1 levels, indicating a critical role for the CL5-NBD2 interface in membrane expression. Gly511 mutation reduced vanadate-induced ADP trapping, indicating altered catalytic activity without affecting ATP binding.\",\n      \"method\": \"Site-directed mutagenesis, immunoblotting, plasma membrane expression assays, 32P-azido-ATP binding and vanadate-induced trapping assays, vesicular transport assays in HEK cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis with multiple orthogonal biochemical readouts (expression, ATPase, transport) in one study\",\n      \"pmids\": [\"21177244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Glu521 and Glu535 in CL5 of MRP1/ABCC1 are differentially required for proper interdomain folding and transport function. E521A and E535A mutants misfold and are degraded by the proteasome; chemical chaperone 4-PBA rescues plasma membrane expression of both but reveals distinct conformational defects: E535A shows reduced substrate affinity affecting both halves of the transporter, while E521A shows altered ATP interactions and a distinct conformational change in the COOH-proximal half.\",\n      \"method\": \"Site-directed mutagenesis, proteasome inhibitor and chemical chaperone rescue (4-PBA), immunoblotting, confocal microscopy, vesicular transport assays, conformational antibody studies in HEK cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis with multiple orthogonal rescue and functional analyses revealing differential domain-specific folding requirements\",\n      \"pmids\": [\"22232552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Transmembrane helices 8 and 9 and portions of cytoplasmic loops 4 and 5 of MRP1/ABCC1 (particularly Tyr440) are critical for binding and transport of glutathione conjugates including LTC4. Substitution of Tyr440 with Phe (as in MRP3) reduced LTC4 and GSH-stimulated estrone-3-sulfate transport by increasing Km for LTC4 5-fold and substantially reducing photolabeling by [3H]LTC4 and azidophenacyl-[35S]GSH.\",\n      \"method\": \"MRP1/MRP3 chimeric protein construction, site-directed mutagenesis, vesicular transport assays, photoaffinity labeling with [3H]LTC4 and azidophenacyl-[35S]GSH\",\n      \"journal\": \"Drug metabolism and disposition: the biological fate of chemicals\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — chimeric protein mapping combined with point mutagenesis and photoaffinity labeling, multiple substrates tested\",\n      \"pmids\": [\"18775981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ABCC1 exports corticosterone but not cortisol, whereas ABCB1 exports cortisol but not corticosterone. ABCC1 (but not ABCB1) is expressed in human adipose tissue; ABCC1 inhibition with probenecid or Abcc1 knockout in mice increased intracellular corticosterone but not cortisol in adipose, sufficient to induce glucocorticoid-responsive gene transcription.\",\n      \"method\": \"ABCC1 pharmacological inhibition (probenecid), Abcc1 knockout mice, corticosteroid infusion in adrenalectomized animals, mass spectrometry measurement of steroid concentrations, glucocorticoid-responsive gene expression in adipose\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout and pharmacological inhibition with orthogonal steroid measurement and gene expression readouts, replicated across mouse models and human adipocytes\",\n      \"pmids\": [\"27535620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Phosphorylation of Tyr920/Ser921 and N-linked glycosylation at Asn19/Asn23 of MRP1/ABCC1 selectively modify As(GS)3 transport kinetics. Phosphorylation-mimicking double mutation Tyr920/Ser921 switches MRP1 to a lower-affinity, higher-capacity As(GS)3 transporter; glycosylation at Asn19/Asn23 increases substrate affinity. Cross-talk between these two modifications was demonstrated: phosphorylation-mimicking substitutions abrogated the effect of Asn19/23Gln glycosylation on As(GS)3 kinetics.\",\n      \"method\": \"Site-directed mutagenesis of glycosylation (N19Q, N23Q, N1006Q) and phosphorylation (Y920F, S921A, and combinations) sites; membrane vesicle transport assays with As(GS)3; prepared with/without phosphatase inhibitors in HEK293 and HeLa cells\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis of PTM sites with in vitro transport kinetics in two cell lines, phosphatase inhibitor controls, and epistatic double-mutant analysis\",\n      \"pmids\": [\"27297967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MRP1/ABCC1 Ala989Thr (SNP) causes a significant decrease in estradiol 17β-glucuronide transport due to decreased apparent affinity (increased Km), as determined by vesicular transport assays in HEK cells transfected with site-directed mutants. Nine other naturally occurring missense variants did not substantially alter transport function.\",\n      \"method\": \"Site-directed mutagenesis recreating 10 SNPs, transient transfection in HEK cells, vesicular transport assays, immunoblotting\",\n      \"journal\": \"Pharmacogenetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro transport reconstitution with mutagenesis, single lab\",\n      \"pmids\": [\"16041243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Collagen/β1 integrin signaling upregulates ABCC1 expression and function via the ERK/MAPK pathway and requires actin polymerization. Inhibition or knockdown of ABCC1 prevented collagen-mediated reduction of intracellular doxorubicin and collagen-mediated protection from doxorubicin-induced apoptosis in leukemic T-cells.\",\n      \"method\": \"β1 integrin signaling with collagen/fibronectin, ERK inhibitor and siRNA knockdown, ABCC1 knockdown, intracellular doxorubicin measurement, apoptosis assays in Jurkat and HSB2 cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis with knockdown studies, multiple inhibitor/siRNA approaches with defined molecular readout, single lab\",\n      \"pmids\": [\"22787275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"MRP1/ABCC1 gene expression is induced by pro-oxidants (tert-butylhydroquinone, DMNO, menadione) that increase intracellular reactive oxygen intermediates (ROI). Elevated intracellular GSH (via γ-GCSh overexpression) suppresses endogenous MRP1 and γ-GCSh expression by reducing ROI levels, indicating that intracellular ROI levels regulate MRP1 expression.\",\n      \"method\": \"Pro-oxidant treatment, flow cytometry (ROI measurement with dihydrorhodamine 123), stable γ-GCSh-transfected cell lines, Northern blot, GSH depletion experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable transfection epistasis combined with ROI measurement and GSH depletion, single lab, multiple methods\",\n      \"pmids\": [\"9813007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Induction of ABCC1 by oxidative stress (tBHQ) is Nrf2-independent but Keap1-dependent: siRNA-mediated Nrf2 knockdown did not suppress tBHQ-induced ABCC1 mRNA elevation, whereas Keap1-specific siRNA knockdown increased ABCC1 mRNA. By contrast, ABCC2 and ABCG2 induction by tBHQ is Nrf2/Keap1-dependent.\",\n      \"method\": \"siRNA knockdown of Nrf2 and Keap1, real-time PCR for ABC transporter mRNA, tBHQ treatment in HepG2 cells, Nrf2 nuclear translocation assay\",\n      \"journal\": \"Journal of experimental therapeutics & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA epistasis with two independent targets (Nrf2, Keap1) and defined mRNA readout, single lab\",\n      \"pmids\": [\"18038766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MRP1/ABCC1 transporter activity is required for dendritic cell (DC) differentiation. Inhibition of MRP1 (but not P-glycoprotein) during in vitro DC differentiation impaired early DC development, resulting in morphological and phenotypic changes including maintained CD14 expression and decreased CD1a, CD1c, Langerin, CD40, CD86, and HLA-DR expression, and reduced ability to stimulate allogeneic T cells. Endogenous CD1 ligands sulfatide and GM1 were identified as MRP1 substrates, though exogenous addition did not restore DC differentiation.\",\n      \"method\": \"Specific MRP1 inhibitors during in vitro DC differentiation from monocytes, flow cytometry for surface markers, mixed lymphocyte reaction, substrate identification assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological loss-of-function with defined phenotypic and molecular readouts, identification of endogenous substrates, single lab\",\n      \"pmids\": [\"16621983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EFHD2 promotes cisplatin resistance in NSCLC via the NOX4-ROS-ABCC1 axis: EFHD2 overexpression induces NOX4-mediated ROS production, which activates membrane expression of ABCC1 for drug efflux. EFHD2 knockdown reduced ABCC1 membrane expression and improved cisplatin sensitivity; ABCC1 knockdown phenocopied EFHD2 loss.\",\n      \"method\": \"EFHD2 overexpression and knockdown, NOX4 inhibition, ROS measurement, ABCC1 membrane expression by Western blot/flow cytometry, cisplatin resistance assays, murine xenograft model\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis with pathway placement (EFHD2→NOX4→ROS→ABCC1), multiple knockdown/overexpression approaches, in vivo validation, single lab\",\n      \"pmids\": [\"32446175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATF4 directly binds to the ABCC1 promoter region to activate its transcription in pancreatic cancer cells. TGF-β1 secreted by cancer-associated fibroblasts upregulates ATF4 via the SMAD2/3 pathway, which in turn transactivates ABCC1 to drive gemcitabine resistance.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) of ATF4 at ABCC1 promoter, ATF4 silencing, TGF-β1 treatment, SMAD2/3 pathway analysis, gemcitabine resistance assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-confirmed direct promoter binding with pathway epistasis, single lab\",\n      \"pmids\": [\"33782384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NRF2-dependent ABCC1 upregulation in glioblastoma promotes GSH depletion when system xc- is blocked (by Erastin), sensitizing cells to ferroptosis. ABCC1 silencing in T98G-shNRF2 cells reversed GSH depletion and conferred ferroptosis resistance while increasing TMZ sensitivity, establishing ABCC1 as a pro-ferroptotic NRF2 target responsible for collateral sensitivity.\",\n      \"method\": \"NRF2 and ABCC1 siRNA/shRNA silencing, ferroptosis inducers (Erastin, RSL3), Ferrostatin-1 rescue, GSH measurement, cell viability assays in U251MG and T98G glioblastoma cells\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic siRNA experiments with defined mechanistic readout (GSH levels, ferroptosis sensitivity), single lab\",\n      \"pmids\": [\"35803910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A heterozygous missense variant in ABCC1 (p.Asn590Ser) causes nonsyndromic hearing loss. The variant results in altered subcellular distribution (cytomembrane and cytoplasm vs. cytomembrane only for wild-type), unstable mRNA, and decreased efflux capacity, establishing ABCC1 function in cochlea (stria vascularis and auditory nerve) as important for hearing.\",\n      \"method\": \"Genetic linkage analysis, exome sequencing, co-segregation analysis, immunofluorescence localization, real-time qPCR for mRNA stability, flow cytometry efflux assay, cochlear expression by in situ hybridization/immunostaining in mouse\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional validation methods for a disease-linked variant in a family study with cochlear expression data, single lab\",\n      \"pmids\": [\"31273342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MRP1/ABCC1 plays a role in heavy metal detoxification in zebrafish. Overexpression of abcc1 improved survival of embryos exposed to Cd, Hg, and As, while overexpression of a transport-dead mutant (ABCC1-G1420D) sensitized embryos to toxic metals. abcc1 mRNA was induced by CdCl2, HgCl2, Pb(NO3)2, and arsenate in ZF4 cells and embryos.\",\n      \"method\": \"abcc1 overexpression and G1420D mutant expression in zebrafish embryos, heavy metal exposure survival assays, whole-mount in situ hybridization, real-time PCR\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function and loss-of-function (transport-dead mutant) in vivo with survival readout, single lab\",\n      \"pmids\": [\"20842442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MRP1/ABCC1 mediates polarized apical-to-basolateral mercury export in placental epithelial cells, regulates intracellular GSH status, and protects placental cells from methyl mercury-induced oxidative stress, cytotoxicity, and apoptosis. siRNA-mediated MRP1 knockdown in HTR-8/SVneo cells caused mercury accumulation, reduced cell viability, increased apoptosis and oxidative stress.\",\n      \"method\": \"Transwell transport assays in MRP1-overexpressing MDCKII cells, siRNA knockdown in HTR-8/SVneo placental cells, mercury accumulation measurement, GSH status, cell viability, apoptosis and ROS assays, immunofluorescence localization in placental tissue\",\n      \"journal\": \"Archives of toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — polarized transport reconstitution plus siRNA knockdown with multiple cellular readouts, localization validation, single lab\",\n      \"pmids\": [\"32915249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM5c (a histone demethylase) downregulates ABCC1 expression by demethylating H3K4me3 at the ABCC1 transcription start site (TSS). ChIP-qPCR confirmed that both H3K4me3 and KDM5c act on the same TSS region of the ABCC1 gene; KDM5c overexpression decreased ABCC1 mRNA/protein and reduced drug resistance, while KDM5c knockdown increased ABCC1 and drug resistance.\",\n      \"method\": \"KDM5c overexpression and siRNA knockdown, ChIP-qPCR for H3K4me3 and KDM5c at ABCC1 TSS, qPCR and Western blot for ABCC1, MTT drug resistance assay in HCT-8 and RKO colon cancer cells\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-confirmed epigenetic mechanism with gain/loss-of-function validation, single lab\",\n      \"pmids\": [\"30257334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Chinese ABCC1 SNP Arg723Gln significantly reduces MRP1-mediated resistance to daunorubicin, doxorubicin, etoposide, vinblastine, and vincristine in HEK293 and CHO-K1 cells. Thr73Ile reduced resistance to methotrexate and etoposide; Arg1058Gln increased resistance to anthracyclines and etoposide. None of the variants affected MRP1 expression or trafficking.\",\n      \"method\": \"Site-directed mutagenesis recreating 4 SNPs, stable transfection in HEK293 and CHO-K1, immunoblotting, confocal microscopy, MTT drug resistance assay\",\n      \"journal\": \"Pharmacogenetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with functional drug resistance readouts in two cell lines, single lab\",\n      \"pmids\": [\"19214144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Cellular folate status influences the transport activity of MRP1/ABCC1: folate-free conditions decreased MRP1-mediated daunorubicin efflux to 43% of normal, which was restored by leucovorin or folic acid repletion. This occurred without changes in MRP1 protein expression or cellular ATP/ADP pools, suggesting folate acts as a cofactor or allosteric modulator of MRP1 transport activity.\",\n      \"method\": \"MRP1-transfected ovarian carcinoma cells (2008/MRP1), folate deprivation/repletion, benzbromarone (MRP1-specific inhibitor) blockade, daunorubicin efflux assays\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection with specific MRP1 inhibitor and metabolic repletion, single lab\",\n      \"pmids\": [\"15041471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"As(GS)3 transport by MRP1/ABCC1 is modulated by N-linked glycosylation at Asn19/Asn23: glycosylation-deficient mutants display low Km (high affinity) similar to dephosphorylated wild-type, indicating that the default glycosylated form has lower affinity for As(GS)3. Cross-talk with phosphorylation at Tyr920/Ser921 controls transport kinetics.\",\n      \"method\": \"N-glycosylation site mutagenesis (N19Q/N23Q/N1006Q), membrane vesicle transport assays prepared with or without phosphatase inhibitors, in HEK293 and HeLa cells\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis of glycosylation and phosphorylation sites with in vitro kinetic transport assays, two-cell-line validation, phosphatase inhibitor controls (covered in same PMID 27297967 above)\",\n      \"pmids\": [\"27297967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SOX2 transcriptionally upregulates ABCC1 to promote side population (SP) cell chemoresistance to paclitaxel in melanoma. SOX2 knockout depleted SP cells and reduced ABCC1 expression; SOX2 induction upregulated SP cells and ABCC1; ABCC1 knockout increased paclitaxel sensitivity. SOX2 was identified as a transcriptional activator of ABCC1.\",\n      \"method\": \"SOX2 knockout and inducible overexpression, ABCC1 knockout, side population assay (Hoechst 33342 exclusion), paclitaxel cytotoxicity assay, reporter assay for SOX2-ABCC1 transcription in melanoma cell lines\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout and overexpression epistasis with functional and molecular readouts, single lab\",\n      \"pmids\": [\"31883360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ApoE/ApoE receptor-2/c-Jun N-terminal kinase (JNK) pathway regulates ABCC1 expression on cerebral microvessels. Methamphetamine reduced abluminal ABCC1 expression on cerebral microvessels; this was prevented by ApoE receptor-2 inhibition (receptor-associated protein) and inducible nitric oxide synthase inhibition (1400W), indicating ApoE signaling through ApoER2 deactivates JNK1/2 to regulate ABCC1.\",\n      \"method\": \"Methamphetamine treatment in C57BL/6J mice, ApoE receptor-2 inhibitor (RAP), iNOS inhibitor (1400W), Western blots of cerebral microvessel extracts, immunoprecipitation, immunohistochemistry\",\n      \"journal\": \"Stroke\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis in vivo with pathway placement (ApoE→ApoER2→JNK→ABCC1), single lab\",\n      \"pmids\": [\"22426312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ABCC1 is a substrate transporter for COTI-2, a thiosemicarbazone anticancer compound, and confers resistance via efflux. ABCC1 recognition of COTI-2 requires formation of stable, non-reducible copper(II)-glutathione adducts; thiosemicarbazones forming reducible copper complexes with GSH are not ABCC1 substrates.\",\n      \"method\": \"Established COTI-2-resistant cell line (SW480/Coti) with confirmed ABCC1 overexpression, ABCC1 inhibitor reversal, copper complex synthesis and characterization, reduction kinetics with GSH, drug resistance assays\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identification with mechanistic explanation (copper-GSH adduct chemistry), inhibitor rescue, single lab\",\n      \"pmids\": [\"33190481\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ABCC1/MRP1 is an ATP-driven plasma membrane efflux transporter with broad substrate specificity encompassing glutathione (GSH)/glucuronide/sulfate conjugates (including leukotriene C4, As(GS)3), the immunotransmitter cGAMP, sphingosine-1-phosphate, corticosterone, and various xenobiotics; its substrate recognition depends critically on specific transmembrane helices (TM6, 8, 10, 11, 14), cytoplasmic loop 5 and its interface with NBD2, and is modulated by N-linked glycosylation at Asn19/Asn23 and phosphorylation at Tyr920/Ser921; transcriptionally, ABCC1 is regulated by Notch1/CBF1, ATF4/SMAD2/3, SOX2, KDM5c-mediated H3K4me3 demethylation, and oxidative stress/ROI signaling; physiologically, ABCC1 controls STING-dependent innate immune signaling via cGAMP export, tissue-specific glucocorticoid availability (exporting corticosterone but not cortisol in adipose), dendritic cell differentiation, placental mercury detoxification, cochlear homeostasis, and cancer cell redox balance via GSH export.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ABCC1/MRP1 is an ATP-dependent plasma membrane efflux pump with broad substrate specificity that links cellular export of glutathione (GSH) conjugates and signaling lipids to innate immunity, redox homeostasis, hormone availability, and multidrug resistance [#1, #0]. Its prototypical substrate is the GSH conjugate leukotriene C4, and competitive-inhibition kinetics show that diverse compounds — glutathione-platinum complexes, anthracycline-GSH conjugates, and stable copper(II)-GSH thiosemicarbazone adducts — gain recognition at a shared substrate-binding site once conjugated to GSH [#1, #4, #30]. The transporter also exports the STING agonist cGAMP, thereby limiting cell-intrinsic STING signaling and restraining cGAS-dependent autoimmunity [#0], and exports sphingosine-1-phosphate to drive ERK signaling and a SphK1 feed-forward loop promoting breast tumor growth and metastasis [#2, #3]. Substrate handling is governed by specific transmembrane helices (TM6, 8, 10, 11, 14) and cytoplasmic-loop architecture: TM8/TM9 and Tyr440 are required for GSH-conjugate binding, cytoplasmic loop 5 and its interface with NBD2 (residues including Glu521/Glu535) are essential for interdomain folding, plasma-membrane expression, and catalysis, and N-glycosylation at Asn19/Asn23 together with phosphorylation at Tyr920/Ser921 reciprocally tune substrate affinity and transport capacity [#7, #10, #8, #9, #12]. Physiologically, ABCC1 selectively exports corticosterone but not cortisol to control tissue glucocorticoid availability in adipose [#11], detoxifies heavy metals including methylmercury and arsenic-GSH while protecting against oxidative stress [#22, #23], and is required for dendritic cell differentiation [#17]. Transcriptionally it is activated by Notch1/CBF1, ATF4 downstream of TGF-β/SMAD2/3, SOX2, and NRF2/oxidative-stress signaling, and repressed by KDM5c-mediated H3K4me3 demethylation, coupling its expression to chemoresistance and ferroptosis sensitivity in multiple cancers [#5, #19, #28, #20, #24]. A heterozygous p.Asn590Ser variant that mislocalizes the protein and reduces efflux causes nonsyndromic hearing loss [#21].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that MRP1 is an ATP-dependent GS-X pump exporting both a physiological GSH conjugate (LTC4) and a glutathione-drug complex through a shared binding site, defining its core transport mechanism and substrate logic.\",\n      \"evidence\": \"ATP-dependent transport and competitive inhibition kinetics in membrane vesicles from MRP1-overexpressing cells\",\n      \"pmids\": [\"8663001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural identity of the shared binding site\", \"Did not address GSH cotransport requirements for non-conjugated drugs\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Extended the shared-binding-site model by showing anthracyclines become ABCC1 substrates only after glutathionation, explaining how broad chemoresistance arises from GSH conjugation.\",\n      \"evidence\": \"In vitro LTC4 transport competitive inhibition with chemically synthesized GS-anthracycline conjugates\",\n      \"pmids\": [\"9647783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether conjugates are transported intact versus co-transported with GSH not directly shown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed ABCC1 expression is governed by intracellular redox state, linking the transporter to oxidative-stress adaptation rather than constitutive housekeeping.\",\n      \"evidence\": \"Pro-oxidant treatment and γ-GCSh overexpression with ROI and Northern-blot readouts\",\n      \"pmids\": [\"9813007\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the transcription factors mediating ROI-driven induction\", \"Single lab\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapped specific transmembrane proline residues (TM6, 8, 10, 11, 14) and a cytoplasmic-loop proline as critical determinants of organic-anion transport and ATP dependence, beginning the structure-function dissection of substrate handling.\",\n      \"evidence\": \"Alanine-scanning mutagenesis with vesicular transport assays across multiple substrates\",\n      \"pmids\": [\"14722114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of how these helices form the translocation pathway\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated that a natural coding SNP (Ala989Thr) lowers substrate affinity, providing pharmacogenetic evidence that ABCC1 sequence variation alters transport.\",\n      \"evidence\": \"Site-directed mutagenesis of 10 SNPs with vesicular transport assays in HEK cells\",\n      \"pmids\": [\"16041243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Clinical consequence of the variant not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed a developmental role beyond drug efflux: ABCC1 transport activity is required for dendritic cell differentiation, with endogenous CD1 ligands as candidate substrates.\",\n      \"evidence\": \"MRP1-specific pharmacological inhibition during in vitro DC differentiation with surface-marker and MLR readouts\",\n      \"pmids\": [\"16621983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Exogenous substrate addition did not rescue differentiation, leaving the relevant transported molecule unconfirmed\", \"Pharmacological rather than genetic loss-of-function\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Localized GSH-conjugate binding to TM8/TM9 and cytoplasmic loops, identifying Tyr440 as a key residue whose mutation reduces LTC4 affinity and photolabeling.\",\n      \"evidence\": \"MRP1/MRP3 chimeras, point mutagenesis, and photoaffinity labeling with [3H]LTC4 and azido-GSH\",\n      \"pmids\": [\"18775981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether Tyr440 contacts GSH or the conjugated moiety\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified S1P as an ABCC1 export substrate coupling the transporter to ERK signaling, expanding its role into lipid-mediated signal transduction.\",\n      \"evidence\": \"siRNA knockdown and inhibitor studies with S1P export and ERK phosphorylation in MCF-7 cells\",\n      \"pmids\": [\"20110355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ATP-dependent S1P transport not reconstituted\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established cytoplasmic loop 5 and its NBD2 interface as essential for membrane expression and catalysis, distinguishing folding/trafficking determinants from the catalytic cycle.\",\n      \"evidence\": \"Site-directed mutagenesis with expression, azido-ATP trapping, and vesicular transport assays\",\n      \"pmids\": [\"21177244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the CL5-NBD2 interface not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated an in vivo metal-detoxification role using a transport-dead mutant, separating transport activity from mere expression.\",\n      \"evidence\": \"abcc1 and transport-dead G1420D overexpression in zebrafish embryos with heavy-metal survival assays\",\n      \"pmids\": [\"20842442\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian relevance not established in this study\", \"Specific metal-GSH species transported not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined Notch1/CBF1 as a direct transcriptional activator of ABCC1, providing a signaling-to-expression axis underlying drug resistance.\",\n      \"evidence\": \"γ-secretase inhibition, shRNA, promoter-reporter, ChIP, EMSA, and CBF1-site mutagenesis\",\n      \"pmids\": [\"22143792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue contexts where Notch dominates ABCC1 regulation not delineated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved differential folding requirements of CL5 glutamates, showing distinct conformational defects rescuable by chemical chaperone, refining the interdomain assembly model.\",\n      \"evidence\": \"Mutagenesis with proteasome/4-PBA rescue, conformational antibodies, and transport assays\",\n      \"pmids\": [\"22232552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-level conformational changes inferred indirectly via antibody reactivity\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected extracellular matrix signaling to ABCC1, showing collagen/β1-integrin-ERK signaling upregulates the transporter to confer doxorubicin resistance.\",\n      \"evidence\": \"Integrin/ERK inhibition and ABCC1 knockdown with intracellular drug and apoptosis readouts in leukemic T-cells\",\n      \"pmids\": [\"22787275\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional effectors downstream of ERK not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established ABCC1 as a selective glucocorticoid exporter (corticosterone not cortisol), giving it a tissue-specific endocrine function in adipose.\",\n      \"evidence\": \"Probenecid inhibition and Abcc1 knockout mice with mass-spec steroid measurement and glucocorticoid-responsive gene expression\",\n      \"pmids\": [\"27535620\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of corticosterone/cortisol discrimination not determined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed post-translational modifications (glycosylation at Asn19/23, phosphorylation at Tyr920/Ser921) reciprocally and epistatically tune substrate affinity and capacity, adding a regulatory layer to transport.\",\n      \"evidence\": \"Systematic PTM-site mutagenesis with As(GS)3 vesicular transport kinetics and phosphatase-inhibitor controls\",\n      \"pmids\": [\"27297967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinases/phosphatases acting on Tyr920/Ser921 not identified\", \"Generality across other substrates not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified ABCC1 as the effector of a EFHD2-NOX4-ROS axis controlling its membrane localization and cisplatin resistance, integrating redox signaling with transporter trafficking.\",\n      \"evidence\": \"EFHD2/ABCC1 overexpression and knockdown, NOX4 inhibition, ROS measurement, and xenografts\",\n      \"pmids\": [\"32446175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ROS-driven membrane insertion not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed ABCC1 mediates polarized placental mercury export and protects against methylmercury oxidative cytotoxicity, defining a barrier-detoxification role.\",\n      \"evidence\": \"Transwell transport in MDCKII cells, siRNA knockdown in placental cells, mercury/GSH/apoptosis readouts\",\n      \"pmids\": [\"32915249\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo placental contribution not directly tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Clarified substrate-recognition chemistry by showing ABCC1 transports thiosemicarbazones only when they form stable non-reducible copper(II)-GSH adducts, refining the GSH-conjugate recognition rule.\",\n      \"evidence\": \"COTI-2-resistant ABCC1-overexpressing line, inhibitor reversal, and copper-GSH complex characterization\",\n      \"pmids\": [\"33190481\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding-site interactions with the copper adduct not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Added ATF4 (downstream of CAF-derived TGF-β1/SMAD2/3) as a direct transcriptional activator of ABCC1, linking the tumor microenvironment to gemcitabine resistance.\",\n      \"evidence\": \"ATF4 ChIP at ABCC1 promoter, ATF4 silencing, and TGF-β1/SMAD pathway analysis\",\n      \"pmids\": [\"33782384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution versus other activators not assessed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined ABCC1 as the exporter limiting cell-intrinsic STING activation through cGAMP efflux, placing it as a regulator of innate immunity and autoimmunity.\",\n      \"evidence\": \"Reciprocal gain/loss-of-function cGAMP export assays and Trex1-/- mouse epistasis\",\n      \"pmids\": [\"36070769\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cGAMP shares the GSH-conjugate binding site not addressed\", \"Intercellular cGAMP transfer consequences not fully mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed NRF2-driven ABCC1 exports GSH to create collateral ferroptosis sensitivity in glioblastoma when system xc- is blocked, revealing a redox-balance role that can be therapeutically exploited.\",\n      \"evidence\": \"NRF2/ABCC1 silencing with Erastin/RSL3 ferroptosis induction, GSH measurement, and TMZ sensitivity in glioblastoma cells\",\n      \"pmids\": [\"35803910\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo ferroptosis relevance not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified KDM5c-mediated H3K4me3 demethylation at the ABCC1 TSS as an epigenetic repressor, complementing the transcription-factor regulation and linking chromatin state to chemoresistance.\",\n      \"evidence\": \"KDM5c overexpression/knockdown with ChIP-qPCR of H3K4me3 and KDM5c at the ABCC1 TSS and drug-resistance assays\",\n      \"pmids\": [\"30257334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream regulators of KDM5c recruitment unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided direct disease evidence: a heterozygous p.Asn590Ser ABCC1 variant causing mislocalization and reduced efflux underlies nonsyndromic hearing loss, establishing cochlear ABCC1 function in hearing.\",\n      \"evidence\": \"Linkage/exome sequencing with co-segregation, localization, mRNA-stability, efflux assays, and cochlear expression mapping\",\n      \"pmids\": [\"31273342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which efflux loss damages cochlea not defined\", \"Single family/lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the single broad substrate-binding pocket simultaneously accommodates GSH conjugates, cGAMP, S1P, and steroids, and how PTMs and trafficking signals are coordinated in vivo to dictate tissue-specific substrate preference, remains unresolved.\",\n      \"evidence\": \"No discovery in the timeline provides a unifying structural or in vivo integration model\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No atomic-resolution structure of ABCC1 with diverse substrates in the corpus\", \"Physiological hierarchy among competing substrates not established\", \"Coupling between redox-driven trafficking and transcriptional/epigenetic regulation unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 2, 11, 23]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [1, 4, 8]},\n      {\"term_id\": \"GO:0042626\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [8, 18, 21, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [1, 11, 22, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [21, 25, 30]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [15, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}