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Research ArticleArticle

Pim-1 Kinase Protects P-Glycoprotein from Degradation and Enables Its Glycosylation and Cell Surface Expression

Yingqiu Xie, Mehmet Burcu, Douglas E. Linn, Yun Qiu and Maria R. Baer
Molecular Pharmacology August 2010, 78 (2) 310-318; DOI: https://doi.org/10.1124/mol.109.061713
Yingqiu Xie
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Mehmet Burcu
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Douglas E. Linn
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Yun Qiu
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Maria R. Baer
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Abstract

The oncogenic serine/threonine kinase Pim-1 phosphorylates and activates the ATP-binding cassette transporter breast cancer resistance protein (ABCG2). The ABC transporter P-glycoprotein (Pgp; ABCB1) also contains a Pim-1 phosphorylation consensus sequence, and we hypothesized that Pim-1 also regulates Pgp. Pgp is exported from the endoplasmic reticulum (ER) as a 150-kDa species that is glycosylated to 170-kDa Pgp, translocates to the cell surface, and mediates drug efflux; alternatively, 150-kDa Pgp is cleaved to a 130-kDa proteolytic product by ER proteases or undergoes ubiquitination and proteasomal degradation. Pim-1 and Pgp interaction was studied in GST pull-down and phosphorylation in in vitro kinase assays. Pim-1 knockdown and inhibition effects on Pgp expression were studied by immunoblotting and flow cytometry and on Pgp stability by immunoblotting after cycloheximide treatment. Pim-1 directly interacted with and phosphorylated Pgp in intact cells and in vitro. Pim-1 knockdown or inhibition decreased cellular and cell surface 170-kDa Pgp, in association with both transient increase in 130-kDa Pgp and increased Pgp ubiquitination and proteasomal degradation. Pim-1 inhibition also decreased expression of 150-kDa Pgp in the presence of the glycosylation inhibitor 2-deoxy-d-glucose. Finally, Pim-1 inhibition sensitized Pgp-overexpressing cells to doxorubicin. Thus, Pim-1 regulates Pgp expression by protecting 150-kDa Pgp from proteolytic and proteasomal degradation and enabling Pgp glycosylation and cell surface translocation and thus Pgp-mediated drug efflux. Pim-1 inhibitors are entering clinical trials and may provide a novel approach to abrogating drug resistance.

Footnotes

  • This work was funded by the Leukemia and Lymphoma Society Translational Research Award; and by the University of Maryland, Baltimore University of Maryland Medical Group Cancer Research [Grant CH 649 CRF].

  • Y.X. and M.B. are co-first authors.

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

    doi:10.1124/mol.109.061713.

  • ABBREVIATIONS:

    BCRP
    breast cancer resistance protein
    ABC
    ATP-binding cassette
    ER
    endoplasmic reticulum
    Pgp
    P-glycoprotein
    PKC
    protein kinase C
    FCS
    fetal calf serum
    shRNA
    small hairpin RNA
    siRNA
    small interfering RNA
    GST
    glutathione transferase
    2-DG
    2-deoxy-d-glucose
    MG-132
    carbobenzoxy-l-leucyl-l-leucyl-l-leucinal
    CHX
    cycloheximide
    DMSO
    dimethyl sulfoxide
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    PSC-833
    valspodar.

  • Received October 11, 2009.
  • Accepted May 11, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (2)
Molecular Pharmacology
Vol. 78, Issue 2
1 Aug 2010
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Research ArticleArticle

Pim-1 Kinase Protects P-Glycoprotein from Degradation and Enables Its Glycosylation and Cell Surface Expression

Yingqiu Xie, Mehmet Burcu, Douglas E. Linn, Yun Qiu and Maria R. Baer
Molecular Pharmacology August 1, 2010, 78 (2) 310-318; DOI: https://doi.org/10.1124/mol.109.061713

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Research ArticleArticle

Pim-1 Kinase Protects P-Glycoprotein from Degradation and Enables Its Glycosylation and Cell Surface Expression

Yingqiu Xie, Mehmet Burcu, Douglas E. Linn, Yun Qiu and Maria R. Baer
Molecular Pharmacology August 1, 2010, 78 (2) 310-318; DOI: https://doi.org/10.1124/mol.109.061713
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