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Research ArticleCELLULAR AND MOLECULAR

Pharmacologic or Genetic Manipulation of Glutathione S-Transferase P1–1 (GSTπ) Influences Cell Proliferation Pathways

Julie E. Ruscoe, Lilliam A. Rosario, Tieli Wang, Laurent Gaté, Pinar Arifoglu, C. Roland Wolf, Colin J. Henderson, Ze'ev Ronai and Kenneth D. Tew
Journal of Pharmacology and Experimental Therapeutics July 2001, 298 (1) 339-345;
Julie E. Ruscoe
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Lilliam A. Rosario
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Tieli Wang
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Laurent Gaté
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Pinar Arifoglu
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C. Roland Wolf
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Colin J. Henderson
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Ze'ev Ronai
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Kenneth D. Tew
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Abstract

Glutathione S-transferase P1–1 (GSTπ) is an abundant and ubiquitously expressed protein in normal and malignant mammalian tissues and possesses catalytic and ligand binding properties. Our present data suggest that the protein contributes to the regulation of cell proliferation. Mouse embryo fibroblasts (MEFs) isolated from mice with a GSTP1–1 [glutathioneS-transferase P1–1 (isozyme in nonhepatic tissue)] null genotype (GSTπ−/−) doubled their population in 26.2 h versus 33.6 h for the wild type (GSTπ+/+). Retroviral transfection of GSTP1–1 into GSTπ−/− MEF cells slowed the doubling time to 30.4 h. Both early passage and immortalized MEF cells from GSTπ−/− animals expressed significantly elevated activity of extracellular signal-regulated kinases ERK1/ERK2, kinases linked to cell proliferation pathways. In vivo, GSTπ−/−mice had higher basal levels of circulating white blood cells compared with GSTπ+/+. Administration of a peptidomimetic inhibitor of GSTP1–1, TLK199, (γ-glutamyl-S-(benzyl)cysteinyl-R-phenyl glycine diethyl ester), stimulated both lymphocyte production and bone marrow progenitor (colony-forming unit-granulocyte macrophage) proliferation, but only in GSTπ+/+ and not in GSTπ−/− animals. Selection of a resistant clone of an HL60 tumor cell line through chronic exposure to TLK199 resulted in cells with elevated activities of c-Jun NH2 terminal kinase (JNK1) and ERK1/ERK2, and allowed the cells to proliferate under stress conditions that induced high levels of apoptosis in the wild type cells. The in vitro and in vivo data are consistent with the principle that GSTP1–1 influences cell proliferation.

Footnotes

  • ↵1 Current address: AstraZeneca, UK.

  • ↵2 Current address: Food and Drug Administration, Alexandria, VA.

  • This work was supported in part by the National Institutes of Health Grants CA06927 and RR05539; by the National Institutes of Health Grants CA53893 to K.D.T. and CA77389 to Z.R.; and by appropriation from the Commonwealth of Pennsylvania.

  • Abbreviations:
    GSH
    glutathione
    GST
    glutathioneS-transferase
    GSTP1–1
    glutathioneS-transferase P1–1 (isozyme in nonhepatic tissue)
    JNK
    c-Jun NH2 terminal kinase
    TLK199
    γ-glutamyl-S-(benzyl)cysteinyl-R-phenyl glycine diethyl ester
    ROS
    reactive oxygen species
    MEF
    mouse embryo fibroblast
    WT
    wild type
    ERK
    extracellular signal-regulated kinase
    MAP
    mitogen-activated protein
    UV
    ultraviolet
    CFU
    colony-forming unit
    PMA
    phorbol-12-myristate-13-acetate
    GM
    granulocyte-macrophage
    • Received January 16, 2001.
    • Accepted March 15, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 1
1 Jul 2001
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Research ArticleCELLULAR AND MOLECULAR

Pharmacologic or Genetic Manipulation of Glutathione S-Transferase P1–1 (GSTπ) Influences Cell Proliferation Pathways

Julie E. Ruscoe, Lilliam A. Rosario, Tieli Wang, Laurent Gaté, Pinar Arifoglu, C. Roland Wolf, Colin J. Henderson, Ze'ev Ronai and Kenneth D. Tew
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 339-345;

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Research ArticleCELLULAR AND MOLECULAR

Pharmacologic or Genetic Manipulation of Glutathione S-Transferase P1–1 (GSTπ) Influences Cell Proliferation Pathways

Julie E. Ruscoe, Lilliam A. Rosario, Tieli Wang, Laurent Gaté, Pinar Arifoglu, C. Roland Wolf, Colin J. Henderson, Ze'ev Ronai and Kenneth D. Tew
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 339-345;
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