Pharmacologic or genetic manipulation of glutathione S-transferase P1-1 (GST ∏) influences cell proliferation pathways

Julie E. Ruscoe, Liliam A. Rosario, Tieli Wang, Laurent Gate, Pinar Arifoglu, C. Roland Wolf, Colin J. Henderson, Ze'ev Ronai, Kenneth D. Tew

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    152 Citations (Scopus)

    Abstract

    Glutathione S-transferase P1-1 (GST ?) 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 [glutathione S-transferase P1-1 (isozyme in nonhepatic tissue)] null genotype (GST ? (-/-)) doubled their population in 26.2 h versus 33.6 h for the wild type (GST ? (+/+)). Retroviral transfection of GSTP1-1 into GST pi (-/-) MEF cells slowed the doubling time to 30.4 h. Both early passage and immortalized MEF cells from GST ? (-/-) animals expressed significantly elevated activity of extracellular signal-regulated kinases ERK1/ERK2, kinases linked to cell proliferation pathways. in vivo, GST ? (-/-) mice had higher basal levels of circulating white blood cells compared with GST ? (+/+). Administration of a peptidomimetic inhibitor of GSTP1-1, TLK199, (gamma -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 GST ? (+/+) and not in GST ? (-/-) 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.

    Original languageEnglish
    Pages (from-to)339-345
    Number of pages7
    JournalJournal of Pharmacology and Experimental Therapeutics
    Volume298
    Issue number1
    Publication statusPublished - 1 Jul 2001

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