Multidrug Resistance Protein 1 (MRP1, ABCC1), a “Multitasking” ATP-binding Cassette (ABC) Transporter

Cole, Susan P.C.

doi:10.1074/jbc.r114.609248

Cited by 300 publications

(273 citation statements)

References 100 publications

(124 reference statements)

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“…ABC transporters are found in all organisms and have a wide range of endogenous and exogenous substrates. Among the ABC family are the multifunctional 'multidrug resistance' (MDR) transporters of the ABCB, -C, and -G subfamilies, which have primarily been studied for their xenobiotic efflux, because their overexpression in cancer cells leads to drug resistance (Szakacs et al, 2006;Chen and Tiwari, 2011;Cole, 2014). However, in addition to effluxing drugs, these transporters can also contribute to disease by moving signaling molecules that govern morphogenetic behaviors of cells (Fletcher et al, 2010;Henderson et al, 2011;Jin et al, 2014;van de Ven et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

ABCC5 is required for cAMP-mediated hindgut invagination in sea urchin embryos

et al. 2015

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ATP-binding cassette (ABC) transporters are evolutionarily conserved proteins that pump diverse substrates across membranes. Many are known to efflux signaling molecules and are extensively expressed during development. However, the role of transporters in moving extracellular signals that regulate embryogenesis is largely unexplored. Here, we show that a mesodermal ABCC (MRP) transporter is necessary for endodermal gut morphogenesis in sea urchin embryos. This transporter, Sp-ABCC5a (C5a), is expressed in pigment cells and their precursors, which are a subset of the non-skeletogenic mesoderm (NSM) cells. C5a expression depends on Delta/Notch signaling from skeletogenic mesoderm and is downstream of Gcm in the aboral NSM gene regulatory network. Long-term imaging of development reveals that C5a knockdown embryos gastrulate, but ∼90% develop a prolapse of the hindgut by the late prism stage (∼8 h after C5a protein expression normally peaks). Since C5a orthologs efflux cyclic nucleotides, and cAMP-dependent protein kinase (Sp-CAPK/PKA) is expressed in pigment cells, we examined whether C5a could be involved in gastrulation through cAMP transport. Consistent with this hypothesis, membrane-permeable pCPT-cAMP rescues the prolapse phenotype in C5a knockdown embryos, and causes archenteron hyper-invagination in control embryos. In addition, the cAMP-producing enzyme soluble adenylyl cyclase (sAC) is expressed in pigment cells, and its inhibition impairs gastrulation. Together, our data support a model in which C5a transports sAC-derived cAMP from pigment cells to control late invagination of the hindgut. Little is known about the ancestral functions of ABCC5/MRP5 transporters, and this study reveals a novel role for these proteins in mesoderm-endoderm signaling during embryogenesis.

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Section: Introductionmentioning

confidence: 99%

ABCC5 is required for cAMP-mediated hindgut invagination in sea urchin embryos

et al. 2015

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“…In addition to its role in drug resistance, MRP1 is important for the transport of physiologic substrates, including mediators of inflammation such as leukotriene C 4 (LTC 4 ) and the cholestatic steroid 17b-estradiol 17-(b-D-glucuronide) (E 2 17bG) (Cole, 2014a). Furthermore, MRP1 transports a variety of other drugs, toxicants, and carcinogens often conjugated to GSH, glucuronate, or sulfate (Jedlitschky et al, 1996;Leslie et al, 2005;Loe et al, 1996a,b).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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The ATP-binding cassette (ABC) transporter multidrug resistance protein 1 (MRP1/ABCC1) is responsible for the cellular export of a chemically diverse array of xenobiotics and endogenous compounds. Arsenic, a human carcinogen, is a high-affinity MRP1 substrate as arsenic triglutathione [As(GS) 3 ]. In this study, marked differences in As(GS) 3 transport kinetics were observed between MRP1-enriched membrane vesicles prepared from human embryonic kidney 293 (HEK) (K m 3.8 mM and V max 307 pmol/mg per minute) and HeLa (K m 0.32 mM and V max 42 pmol/mg per minute) cells. Mutant MRP1 lacking N-linked glycosylation [Asn19/23/1006Gln; sugar-free (SF)-MRP1] expressed in either HEK293 or HeLa cells had low K m and V max values for As(GS) 3 , similar to HeLa wild-type (WT) MRP1. When prepared in the presence of phosphatase inhibitors, both WT-and SF-MRP1-enriched membrane vesicles had a high K m value for As(GS) 3 (3-6 mM), regardless of the cell line. Kinetic parameters of As(GS) 3 for HEKAsn19/23Gln-MRP1 were similar to those of HeLa/HEK-SF-MRP1and HeLa-WT-MRP1, whereas those of single glycosylation mutants were like those of HEK-WT-MRP1. Mutation of 19 potential MRP1 phosphorylation sites revealed that HEK-Tyr920Phe/ Ser921Ala-MRP1 transported As(GS) 3 like HeLa-WT-MRP1, whereas individual HEK-Tyr920Phe-and -Ser921Ala-MRP1 mutants were similar to HEK-WT-MRP1. Together, these results suggest that Asn19/Asn23 glycosylation and Tyr920/Ser921 phosphorylation are responsible for altering the kinetics of MRP1-mediated As(GS) 3 transport. The kinetics of As(GS) 3 transport by HEK-Asn19/23Gln/Tyr920Glu/Ser921Glu were similar to HEK-WT-MRP1, indicating that the phosphorylation-mimicking substitutions abrogated the influence of Asn19/23Gln glycosylation. Overall, these data suggest that cross-talk between MRP1 glycosylation and phosphorylation occurs and that phosphorylation of Tyr920 and Ser921 can switch MRP1 to a lower-affinity, higher-capacity As(GS) 3 transporter, allowing arsenic detoxification over a broad concentration range.

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“…The scarcity of specific MRP1 inhibitors reflects the fact that there is still no clarity about the benefit of P-gp inhibition in the clinical practice, which retards research efforts to develop MRP1 inhibitors for clinical use [190] . However, the calcium channel blocker verapamil and its derivative NMeOHI2, in addition to the several non-steroidal anti-inflammatory drugs (e.g., indomethacin), have shown collateral sensitivity toward MRP1 overexpressing cells [191,192] .…”

Section: Examples Of Such Inhibitors Are Cyclosporine a [26184-187]mentioning

confidence: 99%

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

Jaramillo¹,

Saig²,

Cloos³

et al. 2018

CDR

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P-glycoprotein (ABCB1), multidrug resistance protein-1 (ABCC1) and breast cancer resistance protein (ABCG2) belong to the ATP-binding cassette (ABC) superfamily of proteins that play an important physiological role in protection of the body from toxic xenobiotics and endogenous metabolites. Beyond this, these transporters determine the toxicity profile of many drugs, and confer multidrug resistance (MDR) in cancer cells associated with a poor treatment outcome of cancer patients.It has long been hypothesized that inhibition of ABC drug efflux transporters will increase drug accumulation and thereby overcome MDR, but until now no approved inhibitor of these transporters is available in the clinic. In this review we present molecular strategies to overcome this type of drug resistance and discuss for each of these strategies their promising value or indicate underlying reasons for their limited success.

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Multidrug Resistance Protein 1 (MRP1, ABCC1), a “Multitasking” ATP-binding Cassette (ABC) Transporter

Cited by 300 publications

References 100 publications

ABCC5 is required for cAMP-mediated hindgut invagination in sea urchin embryos

ABCC5 is required for cAMP-mediated hindgut invagination in sea urchin embryos

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

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

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Multidrug Resistance Protein 1 (MRP1, ABCC1), a “Multitasking” ATP-binding Cassette (ABC) Transporter

Cited by 300 publications

References 100 publications

ABCC5 is required for cAMP-mediated hindgut invagination in sea urchin embryos

ABCC5 is required for cAMP-mediated hindgut invagination in sea urchin embryos

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

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

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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