Abstract
ABC (ATP-binding cassette) transporters have diverse roles in many cellular processes. These diverse roles require the presence of conserved membrane spanning domains and nucleotide binding domains. Bcrp (Abcg2) is a member of the ATP binding cassette family of plasma membrane transporters that was originally discovered for its ability to confer drug resistance in tumor cells. Subsequent studies showed Bcrp expression in normal tissues and high expression in primitive stem cells. Bcrp expression is induced under low oxygen conditions consistent with its high expression in tissues exposed to low oxygen environments. Moreover, Bcrp interacts with heme and other porphyrins. This finding and its regulation by hypoxia suggests it may play a role in protecting cells/tissue from protoporphyrin accumulation under hypoxia. These observations are strengthened by the fact that porphyrins accumulate in tissues of the Bcrp knockout mouse. It is possible that humans with loss of function Bcrp alleles may be more susceptible to porphyrin-induced phototoxicity. We propose that Bcrp plays a role in porphyrin homoeostasis and regulates survival under low oxygen conditions.
Similar content being viewed by others
Abbreviations
- ABC:
-
ATP binding cassette
- BSEP:
-
Bile salt export pump
- Bcrp:
-
Breast cancer resistance protein
- CFTR:
-
Cystic fibrosis transmembrane conductance regulator
- DFO:
-
Desferoxamine
- HIF:
-
Hypoxia inducible factor
- NBD:
-
Nucleotide-binding domain
- PFIC:
-
Progressive familial intrahepatic cholestasis
- PPIX:
-
Protoporphyrin IX
- SNP:
-
Single nucleotide polymorphism
- TMD:
-
Transmembrane domain
References
JD Allen RF Brinkhuis L Deemter Particlevan J Wijnholds AH Schinkel (2000) ArticleTitleExtensive contribution of the multidrug transporters P-glycoprotein and Mrp1 to basal drug resistance Cancer Res 60 5761–5766 Occurrence Handle11059771
JD Allen SC Jackson AH Schinkel (2002) ArticleTitleA mutation hot spot in the Bcrp1 (Abcg2) multidrug transporter in mouse cell lines selected for Doxorubicin resistance Cancer Res 62 2294–2299 Occurrence Handle11956086
R Allikmets LM Schriml A Hutchinson V Romano-Spica M Dean (1998) ArticleTitleA human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance Cancer Res 58 5337–5339 Occurrence Handle9850061
J Bear W Tan AS Zolotukhin C Tabernero EA Hudson BK Felber (1999) ArticleTitleIdentification of novel import and export signals of human TAP, the protein that binds to the constitutive transport element of the type D retrovirus mRNAs Mol Cell Biol 19 6306–6317 Occurrence Handle10454577
C Blom EC Klasen J Steveninck Particlevan (1990) ArticleTitleDifferent characteristics of ferrochelatase in cultured fibroblasts of erythropoietic protoporphyria patients and normal controls Biochim Biophys Acta 1039 339–342 Occurrence Handle2378891
F Bohm R Edge S Foley L Lange TG Truscott (2001) ArticleTitleAntioxidant inhibition of porphyrin-induced cellular phototoxicity J Photochem Photobiol B 65 177–183 Occurrence Handle10.1016/S1011-1344(01)00259-7 Occurrence Handle11809377
DA Brenner JR Bloomer (1980) ArticleTitleThe enzymatic defect in variegate prophyria. Studies with human cultured skin fibroblasts N Engl J Med 302 765–769 Occurrence Handle7354807
C Chen N Pore A Behrooz F Ismail-Beigi A Maity (2001) ArticleTitleRegulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia J Biol Chem 276 9519–9525 Occurrence Handle10.1074/jbc.M010144200 Occurrence Handle11120745
FP Chen H Risheg Y Liu J Bloomer (2002a) ArticleTitleFerrochelatase gene mutations in erythropoietic protoporphyria: focus on liver disease Cell Mol Biol (Noisy.-le-grand) 48 83–89
HL Chen PS Chang HC Hsu YH Ni HY Hsu JH Lee YM Jeng WY Shau MH Chang (2002b) ArticleTitleFIC1 and BSEP defects in Taiwanese patients with chronic intrahepatic cholestasis with low gamma-glutamyltranspeptidase levels J Pediatr 140 119–124 Occurrence Handle10.1067/mpd.2002.119993
ZS Chen RW Robey MG Belinsky I Shchaveleva XQ Ren Y Sugimoto DD Ross SE Bates GD Kruh (2003) ArticleTitleTransport of methotrexate, methotrexate polyglutamates, and 17beta-estradiol 17-(beta-D-glucuronide) by ABCG2: effects of acquired mutations at R482 on methotrexate transport Cancer Res 63 4048–4054 Occurrence Handle12874005
MG Cipolleschi SP Dello M Olivotto (1993) ArticleTitleThe role of hypoxia in the maintenance of hematopoietic stem cells Blood 82 2031–2037 Occurrence Handle8104535
MG Cipolleschi E Rovida Z Ivanovic V Praloran M Olivotto SP Dello (2000) ArticleTitleThe expansion of murine bone marrow cells preincubated in hypoxia as an in vitro indicator of their marrow-repopulating ability Leukemia 14 735–739 Occurrence Handle10.1038/sj.leu.2401744 Occurrence Handle10764163
D Corzo W Gibson K Johnson G Mitchell G LePage GF Cox R Casey C Zeiss H Tyson GR Cutting GV Raymond KD Smith PA Watkins AB Moser HW Moser SJ Steinberg (2002) ArticleTitleContiguous deletion of the X-linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders Am J Hum Genet 70 1520–1531 Occurrence Handle10.1086/340849 Occurrence Handle11992258
KL Covello MC Simon (2004) ArticleTitleHIFs, hypoxia, and vascular development Curr Top Dev Biol 62 37–54 Occurrence Handle15522738
LA Doyle W Yang LV Abruzzo T Krogmann Y Gao AK Rishi DD Ross (1998) ArticleTitleA multidrug resistance transporter from human MCF-7 breast cancer cells Proc Natl Acad Sci USA 95 15665–15670 Occurrence Handle10.1073/pnas.95.26.15665 Occurrence Handle9861027
GD Ewart AJ Howells (1998) ArticleTitleABC transporters involved in transport of eye pigment precursors in Drosophila melanogaster Method Enzymol 292 213–224
N Gaedeke M Klein U Kolukisaoglu C Forestier A Muller M Ansorge D Becker Y Mamnun K Kuchler B Schulz B Mueller-Roeber E Martinoia (2001) ArticleTitleThe Arabidopsis thaliana ABC transporter AtMRP5 controls root development and stomata movement EMBO J 20 1875–1887 Occurrence Handle10.1093/emboj/20.8.1875 Occurrence Handle11296221
MM Gottesman SV Ambudkar (2001) ArticleTitleOverview: ABC transporters and human disease J Bioenerg Biomembr 33 453–458 Occurrence Handle10.1023/A:1012866803188 Occurrence Handle11804186
P Hafkemeyer S Dey SV Ambudkar CA Hrycyna I Pastan MM Gottesman (1998) ArticleTitleContribution to substrate specificity and transport of nonconserved residues in transmembrane domain 12 of human P-glycoprotein Biochemistry 37 16400–16409 Occurrence Handle10.1021/bi980871+ Occurrence Handle9819232
CF Higgins KJ Linton (2004) ArticleTitleThe ATP switch model for ABC transporters Nat Struct Mol Biol 11 918–926 Occurrence Handle10.1038/nsmb836 Occurrence Handle15452563
T Hofer RH Wenger MF Kramer GC Ferreira M Gassmann (2003) ArticleTitleHypoxic up-regulation of erythroid 5-aminolevulinate synthase Blood 101 348–350 Occurrence Handle10.1182/blood-2002-03-0773 Occurrence Handle12393745
DL Hogue L Liu V Ling (1999) ArticleTitleIdentification and characterization of a mammalian mitochondrial ATP-binding cassette membrane protein J Mol Biol 285 379–389 Occurrence Handle10.1006/jmbi.1998.2259 Occurrence Handle9878413
Y Honjo CA Hrycyna QW Yan WY Medina-Perez RW Robey LA de Particlevan T Litman M Dean SE Bates (2001) ArticleTitleAcquired mutations in the MXR/BCRP/ABCP gene alter substrate specificity in MXR/BCRP/ABCP-overexpressing cells Cancer Res 61 6635–6639 Occurrence Handle11559526
G Hopfl O Ogunshola M Gassmann (2004) ArticleTitleHIFs and tumors–causes and consequences Am J Physiol Regulate Integrate Comp Physiol 286 R608–R623 Occurrence Handle10.1152/ajpregu.00538.2003
Y Imai M Nakane K Kage S Tsukahara E Ishikawa T Tsuruo Y Miki Y Sugimoto (2002) ArticleTitleC421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q141K protein and low-level drug resistance Mol Cancer Ther 1 611–616 Occurrence Handle12479221
DR Johnson RA Finch ZP Lin CJ Zeiss AC Sartorelli (2001) ArticleTitleThe pharmacological phenotype of combined multidrug-resistance mdr1a/1b- and mrp1-deficient mice Cancer Res 61 1469–1476 Occurrence Handle11245453
JW Jonker M Buitelaar E Wagenaar MA VanDer Valk GL Scheffer RJ Scheper T Plosch F Kuipers RP Elferink H Rosing JH Beijnen AH Schinkel (2002) ArticleTitleThe breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria Proc Natl Acad Sci USA 99 15649–15654 Occurrence Handle10.1073/pnas.202607599 Occurrence Handle12429862
K Kage S Tsukahara T Sugiyama S Asada E Ishikawa T Tsuruo Y Sugimoto (2002) ArticleTitleDominant-negative inhibition of breast cancer resistance protein as drug efflux pump through the inhibition of S-S dependent homodimerization Int J Cancer 97 626–630 Occurrence Handle10.1002/ijc.10100 Occurrence Handle11807788
CJ Ketchum WK Schmidt GV Rajendrakumar S Michaelis PC Maloney (2001) ArticleTitleThe yeast a-factor transporter Ste6p, a member of the ABC superfamily, couples ATP hydrolysis to pheromone export J Biol Chem 276 29007–29011 Occurrence Handle10.1074/jbc.M100810200 Occurrence Handle11389139
P Krishnamurthy DD Ross T Nakanishi K Bailey-Dell S Zhou KE Mercer B Sarkadi BP Sorrentino JD Schuetz (2004) ArticleTitleThe stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme J Biol Chem 279 24218–24225 Occurrence Handle10.1074/jbc.M313599200 Occurrence Handle15044468
HW Lim (1989) ArticleTitleMechanisms of phototoxicity in porphyria cutanea tarda and erythropoietic protoporphyria Immunol Ser 46 671–685 Occurrence Handle2488874
T Litman U Jensen A Hansen KM Covitz Z Zhan P Fetsch A Abati PR Hansen T Horn T Skovsgaard SE Bates (2002) ArticleTitleUse of peptide antibodies to probe for the mitoxantrone resistance-associated protein MXR/BCRP/ABCP/ABCG2 Biochim Biophys Acta 1565 6–16 Occurrence Handle12225847
TW Loo DM Clarke (1999) ArticleTitleIdentification of residues in the drug-binding domain of human P-glycoprotein. Analysis of transmembrane segment 11 by cysteine-scanning mutagenesis and inhibition by dibromobimane J Biol Chem 274 35388–35392 Occurrence Handle10.1074/jbc.274.50.35388 Occurrence Handle10585407
M Miwa S Tsukahara E Ishikawa S Asada Y Imai Y Sugimoto (2003) ArticleTitleSingle amino acid substitutions in the transmembrane domains of breast cancer resistance protein (BCRP) alter cross resistance patterns in transfectants Int J Cancer 107 757–763 Occurrence Handle10.1002/ijc.11484 Occurrence Handle14566825
K Miyake L Mickley T Litman Z Zhan R Robey B Cristensen M Brangi L Greenberger M Dean T Fojo SE Bates (1999) ArticleTitleMolecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: demonstration of homology to ABC transport genes Cancer Res 59 8–13 Occurrence Handle9892175
S Mizuarai N Aozasa H Kotani (2004) ArticleTitleSingle nucleotide polymorphisms result in impaired membrane localization and reduced atpase activity in multidrug transporter ABCG2 Int J Cancer 109 238–246 Occurrence Handle10.1002/ijc.11669 Occurrence Handle14750175
A Ouiddir C Planes I Fernandes A VanHesse C Clerici (1999) ArticleTitleHypoxia up-regulates activity and expression of the glucose transporter GLUT1 in alveolar epithelial cells Am J Resp Cell Mol Biol 21 710–718
C Ozvegy T Litman G Szakacs Z Nagy S Bates A Varadi B Sarkadi (2001) ArticleTitleFunctional characterization of the human multidrug transporter, ABCG2, expressed in insect cells Biochem Biophys Res Commun 285 111–117 Occurrence Handle10.1006/bbrc.2001.5130 Occurrence Handle11437380
C Ozvegy A Varadi B Sarkadi (2002) ArticleTitleCharacterization of drug transport, ATP hydrolysis, and nucleotide trapping by the human ABCG2 multidrug transporter. Modulation of substrate specificity by a point mutation J Biol Chem 277 47980–47990 Occurrence Handle10.1074/jbc.M207857200 Occurrence Handle12374800
JR Riordan JM Rommens B Kerem N Alon R Rozmahel Z Grzelczak J Zielenski S Lok N Plavsic JL Chou (1989) ArticleTitleIdentification of the cystic fibrosis gene: cloning and characterization of complementary DNA Science 245 1066–1073
RW Robey K Steadman O Polgar K Morisaki M Blayney P Mistry SE Bates (2004) ArticleTitlePheophorbide a is a specific probe for ABCG2 function and inhibition Cancer Res 64 1242–1246 Occurrence Handle14973080
E Rocchi A Khodjakov EL Volk CH Yang T Litman SE Bates E Schneider (2000) ArticleTitleThe product of the ABC half-transporter gene ABCG2 (BCRP/MXR/ABCP) is expressed in the plasma membrane Biochem Biophys Res Commun 271 42–46 Occurrence Handle10.1006/bbrc.2000.2590 Occurrence Handle10777678
G Russ F Esquivel JW Yewdell P Cresswell T Spies JR Bennink (1995) ArticleTitleAssembly, intracellular localization, and nucleotide binding properties of the human peptide transporters TAP1 and TAP2 expressed by recombinant vaccinia viruses J Biol Chem 270 21312–21318 Occurrence Handle10.1074/jbc.270.36.21312 Occurrence Handle7673167
GL Scheffer M Maliepaard AC Pijnenborg MA Gastelen Particlevan MC Jong Particlede AB Schroeijers DM Van Der Kolk JD Allen DD Ross P van der Valk WS Dalton JH Schellens RJ Scheper (2000) ArticleTitleBreast cancer resistance protein is localized at the plasma membrane in mitoxantrone- and topotecan-resistant cell lines Cancer Res 60 2589–2593 Occurrence Handle10825126
JH Schellens RJ Scheper (2000) ArticleTitleBreast cancer resistance protein is localized at the plasma membrane in mitoxantrone- and topotecan-resistant cell lines Cancer Res 60 2589–2593 Occurrence Handle10825126
TN Seagroves HE Ryan H Lu BG Wouters M Knapp P Thibault K Laderoute RS Johnson (2001) ArticleTitleTranscription factor HIF-1 is a necessary mediator of the pasteur effect in mammalian cells Mol Cell Biol 21 3436–3444 Occurrence Handle10.1128/MCB.21.10.3436-3444.2001 Occurrence Handle11313469
GL Semenza (2001) ArticleTitleHIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus Cell 107 1–3 Occurrence Handle10.1016/S0092-8674(01)00518-9 Occurrence Handle11595178
GL Semenza PH Roth HM Fang GL Wang (1994) ArticleTitleTranscriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1 J Biol Chem 269 23757–23763
Y Shimada S Okuno A Kawai H Shinomiya A Saito M Suzuki Y Omori N Nishino N Kanemoto T Fujiwara M Horie E Takahashi (1998) ArticleTitleCloning and chromosomal mapping of a novel ABC transporter gene (hABC7), a candidate for X-linked sideroblastic anemia with spinocerebellar ataxia J␣Hum Genet 43 115–122 Occurrence Handle10.1007/s100380050051 Occurrence Handle9621516
AR Tanaka K Tanabe M Morita M Kurisu Y Kasiwayama M Matsuo N Kioka T Amachi T Imanaka K Ueda (2002) ArticleTitleATP binding/hydrolysis by and phosphorylation of peroxisomal ATP-binding cassette proteins PMP70 (ABCD3) and adrenoleukodystrophy protein (ABCD1) J Biol Chem 277 40142–40147 Occurrence Handle10.1074/jbc.M205079200 Occurrence Handle12176987
R Thompson S Strautnieks (2001) ArticleTitleBSEP: function and role in progressive familial intrahepatic cholestasis Semin Liver Dis 21 545–550 Occurrence Handle10.1055/s-2001-19038 Occurrence Handle11745042
N Uchida FY Leung CJ Eaves (2002) ArticleTitleLiver and marrow of adult mdr-1a/1b(-/-) mice show normal generation, function, and multi-tissue trafficking of primitive hematopoietic cells Exp Hematol 30 862–869 Occurrence Handle10.1016/S0301-472X(02)00879-2 Occurrence Handle12160837
EL Volk KM Farley Y Wu F Li RW Robey E Schneider (2002) ArticleTitleOverexpression of wild-type breast cancer resistance protein mediates methotrexate resistance Cancer Res 62 5035–5040 Occurrence Handle12208758
GL Wang BH Jiang EA Rue GL Semenza (1995) ArticleTitleHypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension Proc Natl Acad Sci USA 92 5510–5514 Occurrence Handle7539918
J Wijnholds R Evers MR Leusden Particlevan CA Mol GJ Zaman U Mayer JH Beijnen P Van der Valk P Krimpenfort P Borst (1997) ArticleTitleIncreased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein Nat Med 3 1275–1279 Occurrence Handle10.1038/nm1197-1275 Occurrence Handle9359705
CP Zamber JK Lamba K Yasuda J Farnum K Thummel JD Schuetz EG Schuetz (2003) ArticleTitleNatural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine Pharmacogenetics 13 19–28 Occurrence Handle10.1097/00008571-200301000-00004 Occurrence Handle12544509
DW Zhang HM Gu D Situ A Haimeur SP Cole RG Deeley (2003) ArticleTitleFunctional importance of polar and charged amino acid residues in transmembrane helix 14 of multidrug resistance protein 1 (MRP1/ABCC1): identification of an aspartate residue critical for conversion from a high to low affinity substrate binding state J Biol Chem 278 46052–46063 Occurrence Handle10.1074/jbc.M308403200 Occurrence Handle12954620
S Zhou JJ Morris Y Barnes L Lan JD Schuetz BP Sorrentino (2002) ArticleTitleBcrp1 gene expression is required for normal numbers of side population stem cells in mice, and aconfers␣relative protection to mitoxantrone in hematopoietic cells in␣vivo Proc Natl Acad Sci USA 99 12339–12344 Occurrence Handle10.1073/pnas.192276999 Occurrence Handle12218177
S Zhou JD Schuetz KD Bunting AM Colapietro J Sampath JJ Morris I Lagutina GC Grosveld M Osawa H Nakauchi BP Sorrentino (2001) ArticleTitleThe ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype Nat Med 7 1028–1034 Occurrence Handle10.1038/nm0901-1028 Occurrence Handle11533706
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Krishnamurthy, P., Schuetz, J.D. The ABC Transporter Abcg2/Bcrp: Role in Hypoxia Mediated Survival. Biometals 18, 349–358 (2005). https://doi.org/10.1007/s10534-005-3709-7
Issue Date:
DOI: https://doi.org/10.1007/s10534-005-3709-7