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Research ArticleArticle

Receptor for Activated C-Kinase 1 Regulates the Cell Surface Expression and Function of ATP Binding Cassette G2

Yuki Ikebuchi, Kousei Ito, Tappei Takada, Naohiko Anzai, Yoshikatsu Kanai and Hiroshi Suzuki
Drug Metabolism and Disposition December 2010, 38 (12) 2320-2328; DOI: https://doi.org/10.1124/dmd.110.034603
Yuki Ikebuchi
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Kousei Ito
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Tappei Takada
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Naohiko Anzai
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Yoshikatsu Kanai
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Hiroshi Suzuki
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Abstract

In a previous report, we identified the receptor for activated C-kinase 1 (RACK1) as a positive regulator of the cellular localization and expression of ATP-binding cassette B4, a phosphatidylcholine translocator expressed on the bile canalicular membrane. In the present study, we focused on the role of RACK1 on ATP-binding cassette G2 (ABCG2), which is responsible for the cellular extrusion of compounds including antitumor drugs. Protein expression of ABCG2 was up-regulated by RACK1 overexpression, although mRNA expression of ABCG2 was not dependent on RACK1. The effect of RACK1 on the expression of ABCG2 on the cell surface was confirmed by the uptake of [3H]estrone sulfate, an ABCG2 substrate, into isolated membrane vesicles. The expression of RACK1 affected cellular resistance to mitoxantrone, an anticancer drug excreted by ABCG2, and this effect of RACK1 was abolished in the presence of fumitremorgin C, a selective ABCG2 inhibitor. These results suggest that RACK1 has functional significance as a regulatory cofactor of ABCG2 and is indispensable for the cell surface expression and excretion function of ABCG2. The precise mechanism for RACK1-dependent expression of ABCG2 remains to be clarified, because the results of N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132) and chloroquine treatment and those of metabolic labeling experiments did not give us clear evidence whether the reduction of ABCG2 expression in RACK1-knocked down cells may be caused by the suppression of ABCG2 protein synthesis or by acceleration of its degradation.

Footnotes

  • This work was supported in part by the Ministry of Education, Science and Culture of Japan [Grant-in-Aid 17081006 for Scientific Research on Priority Areas].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.034603.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    ABC
    ATP-binding cassette
    RACK1
    receptor for activated C-kinase 1
    siRNA
    small interfering RNA
    PKC
    protein kinase C
    SN-38
    7-ethyl-10-hydroxycamptothecin
    E1S
    estrone sulfate
    FTC
    fumitremorgin C
    LAMP1
    lysosomal-associated membrane protein
    PCR
    polymerase chain reaction
    MEM
    minimum essential medium
    FBS
    fetal bovine serum
    EGFP
    enhanced green fluorescent protein
    PBS
    phosphate-buffered saline
    miRNA
    microRNA
    RIPA
    radioimmunoprecipitation assay
    MG132
    N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5, diphenyltetrazolium bromide.

  • Received May 20, 2010.
  • Accepted September 21, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (12)
Drug Metabolism and Disposition
Vol. 38, Issue 12
1 Dec 2010
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Research ArticleArticle

Receptor for Activated C-Kinase 1 Regulates the Cell Surface Expression and Function of ATP Binding Cassette G2

Yuki Ikebuchi, Kousei Ito, Tappei Takada, Naohiko Anzai, Yoshikatsu Kanai and Hiroshi Suzuki
Drug Metabolism and Disposition December 1, 2010, 38 (12) 2320-2328; DOI: https://doi.org/10.1124/dmd.110.034603

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Research ArticleArticle

Receptor for Activated C-Kinase 1 Regulates the Cell Surface Expression and Function of ATP Binding Cassette G2

Yuki Ikebuchi, Kousei Ito, Tappei Takada, Naohiko Anzai, Yoshikatsu Kanai and Hiroshi Suzuki
Drug Metabolism and Disposition December 1, 2010, 38 (12) 2320-2328; DOI: https://doi.org/10.1124/dmd.110.034603
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