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The expressions of ABCC4 and ABCG2 xenobiotic transporters in human keratinocytes are proliferation-related

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Abstract

Xenobiotic transporters of the ATP-binding cassette (ABC) protein superfamily play important roles in maintaining the biochemical barrier of various tissues, but their precise functions in the skin are not yet known. Screening of the expressions of the known xenobiotic transporter genes in two in vitro keratinocyte differentiation models revealed that the ABCC4 and ABCG2 transporters are highly expressed in proliferating keratinocytes, their expressions decreasing along with differentiation. Abrogation of the ABCC4 and ABCG2 protein functions by siRNA-mediated silencing and chemical inhibition did not affect the proliferation of HaCaT cells. In contrast, disruption of the ABCG2 function had no effect on normal human epidermal keratinocyte proliferation, while the inhibition of ABCC-type transporters by probenecid resulted in a striking decrease in the proliferation of the cells. These results indicate that, besides their possible therapy-modulating effects, xenobiotic transporters may contribute significantly to other keratinocyte functions, such as cell proliferation.

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Abbreviations

ABC:

ATP-binding cassette

NHKs:

Normal human epidermal keratinocytes

ITGA5:

Integrin alpha 5

KRT1:

Keratin 1

IVL:

Involucrin

References

  1. Allen JD, van Loevezijn A, Lakhai JM, van der Valk M, van Tellingen O, Reid G, Schellens JHM, Koomen GJ, Schinkel AH (2002) Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C. Mol Cancer Ther 1:417–425

    Article  PubMed  CAS  Google Scholar 

  2. Bailey-Dell KJ, Hassel B, Doyle LA, Ross DD (2001) Promoter characterization and genomic organization of the human breast cancer resistance protein (ATP-binding cassette transporter G2) gene. Biochim Biophys Acta 1520:234–241

    PubMed  CAS  Google Scholar 

  3. Baron JM, Holler D, Schiffer R, Frankenberg S, Neis M, Merk HF, Jugert FK (2001) Expression of multiple cytochrome p450 enzymes and multidrug resistance-associated transport proteins in human skin keratinocytes. J Invest Dermatol 116:541–548

    Article  PubMed  CAS  Google Scholar 

  4. Borst P, Elferink RO (2002) Mammalian ABC transporters in health and disease. Annu Rev Biochem 71:537–592

    Article  PubMed  CAS  Google Scholar 

  5. Chen Z, Liu F, Ren Q, Zhao Q, Ren H, Lu S, Zhang L, Han Z (2010) Suppression of ABCG2 inhibits cancer cell proliferation. Int J Cancer 126:841–851

    PubMed  CAS  Google Scholar 

  6. Choi CH (2005) ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell Int 5:30–42

    Article  PubMed  Google Scholar 

  7. Copsel S, Garcia CI, Diez F, Vermeulen M, Baldi A, Bianciotti LG, Russel FG, Shayo C, Davio C (2011) Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation. J Biol Chem (in press)

  8. Kielar D, Kaminski WE, Liebisch G, Piehler A, Wenzel JJ, Mohle C, Heimerl S, Langmann T, Friedrich SO, Bottcher A, Barlage S, Drobnik W, Schmitz G (2003) Adenosine triphosphate binding cassette (ABC) transporters are expressed and regulated during terminal keratinocyte differentiation: a potential role for ABCA7 in epidermal lipid reorganization. J Invest Dermatol 121:465–474

    Article  PubMed  CAS  Google Scholar 

  9. Kinyo A, Kiss-Laszlo Z, Hambalko S, Bebes A, Kiss M, Szell M, Bata-Csorgo Z, Nagy F, Kemeny L (2010) COP1 contributes to UVB-induced signaling in human keratinocytes. J Invest Dermatol 130:541–545

    Article  PubMed  CAS  Google Scholar 

  10. Krishnamurthy P, Schuetz JD (2006) Role of ABCG2/BCRP in biology and medicine. Annu Rev Pharmacol Toxicol 46:381–410

    Article  PubMed  CAS  Google Scholar 

  11. Leslie EM, Deeley RG, Cole SP (2005) Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol 204:216–237

    Article  PubMed  CAS  Google Scholar 

  12. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408

    Article  PubMed  CAS  Google Scholar 

  13. Merk HF, Jugert FK, Frankenberg S (1996) Biotransformation in the skin. In: Marzulli FN, Maibach H (eds) Dermatotoxicology. Taylor & Francis, Washington, pp 61–73

    Google Scholar 

  14. Pivarcsi A, Szell M, Kemeny L, Dobozy A, Bata-Csorgo Z (2001) Serum factors regulate the expression of the proliferation-related genes alpha5 integrin and keratin 1, but not keratin 10, in HaCaT keratinocytes. Arch Dermatol Res 293:206–213

    Article  PubMed  CAS  Google Scholar 

  15. Sassi Y, Lipskaia L, Vandecasteele G, Nikolaev VO, Hatem SN, Cohen AF, Russel FG, Mougenot N, Vrignaud C, Lechat P, Lompre AM, Hulot JS (2008) Multidrug resistance-associated protein 4 regulates cAMP-dependent signaling pathways and controls human and rat SMC proliferation. J Clin Invest 118:2747–2757

    Article  PubMed  CAS  Google Scholar 

  16. Scotto KW (2003) Transcriptional regulation of ABC drug transporters. Oncogene 22:7496–7511

    Article  PubMed  CAS  Google Scholar 

  17. Smith G, Dawe RS, Clark C, Evans AT, Comrie MM, Wolf CR, Ferguson J, Ibbotson SH (2003) Quantitative real-time reverse transcription-polymerase chain reaction analysis of drug metabolizing and cytoprotective genes in psoriasis and regulation by ultraviolet radiation. J Invest Dermatol 121:390–398

    Article  PubMed  CAS  Google Scholar 

  18. Sonkoly E, Bata-Csorgo Z, Pivarcsi A, Polyanka H, Kenderessy-Szabo A, Molnar G, Szentpali K, Bari L, Megyeri K, Mandi Y, Dobozy A, Kemeny L, Szell M (2005) Identification and characterization of a novel, psoriasis susceptibility-related noncoding RNA gene, PRINS. J Biol Chem 280:24159–24167

    Article  PubMed  CAS  Google Scholar 

  19. Tompkins LM, Li H, Li L, Lynch C, Xie Y, Nakanishi T, Ross DD, Wang H (2010) A novel xenobiotic responsive element regulated by aryl hydrocarbon receptor is involved in the induction of BCRP/ABCG2 in LS174T cells. Biochem Pharmacol 80:1754–1761

    Article  PubMed  CAS  Google Scholar 

  20. van Aubel RA, Smeets PH, Peters JG, Bindels RJ, Russel FG (2002) The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP. J Am Soc Nephrol 13:595–603

    PubMed  Google Scholar 

  21. Xu S, Weerachayaphorn J, Cai SY, Soroka CJ, Boyer JL (2010) Aryl hydrocarbon receptor and NF-E2-related factor 2 are key regulators of human MRP4 expression. Am J Physiol Gastrointest Liver Physiol 299:G126–G135

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants Asbóth XTTPSRT1, OTKA NK77434, OTKA K61541, OTKA K68680, TÁMOP-4.2.2-08/1-2008-0001 and TÁMOP-4.2.2/B-10/1-2010-0012.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Dermatology and Allergology, Faculty of Medicine, University of Szeged, Korányi fasor 6, Szeged, 6720, Hungary

    Attila Bebes, Kornélia Kis, Zsuzsanna Bata-Csörgő, Lajos Kemény & Attila Dobozy

  2. SOLVO Biotechnology, Szeged, Hungary

    Tünde Nagy & Anita Kurunczi

  3. Dermatological Research Group of the Hungarian Academy of Sciences, University of Szeged, Szeged, Hungary

    Hilda Polyánka, Zsuzsanna Bata-Csörgő, Lajos Kemény, Attila Dobozy & Márta Széll

Authors
  1. Attila Bebes
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  2. Kornélia Kis
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  3. Tünde Nagy
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  4. Anita Kurunczi
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  5. Hilda Polyánka
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  7. Lajos Kemény
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  8. Attila Dobozy
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  9. Márta Széll
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Correspondence to Attila Bebes.

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Bebes, A., Kis, K., Nagy, T. et al. The expressions of ABCC4 and ABCG2 xenobiotic transporters in human keratinocytes are proliferation-related. Arch Dermatol Res 304, 57–63 (2012). https://doi.org/10.1007/s00403-011-1174-4

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  • DOI: https://doi.org/10.1007/s00403-011-1174-4

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