title: Pharmacologic or genetic manipulation of glutathione S-transferase P1-1 (GSTpi) influences cell proliferation pathways.
abstract: Glutathione S-transferase P1-1 (GSTpi) 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 (GSTpi(-/-)) doubled their population in 26.2 h versus 33.6 h for the wild type (GSTpi(+/+)). Retroviral transfection of GSTP1-1 into GSTpi(-/-) MEF cells slowed the doubling time to 30.4 h. Both early passage and immortalized MEF cells from GSTpi(-/-) animals expressed significantly elevated activity of extracellular signal-regulated kinases ERK1/ERK2, kinases linked to cell proliferation pathways. In vivo, GSTpi(-/-) mice had higher basal levels of circulating white blood cells compared with GSTpi(+/+). 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 GSTpi(+/+) and not in GSTpi(-/-) 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.
authors.affiliation: Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Ruscoe
authors.forename: L A
authors.initials: LA
authors.lastname: Rosario
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.forename: L
authors.initials: L
authors.lastname: Gaté
authors.forename: P
authors.initials: P
authors.lastname: Arifoglu
authors.forename: C R
authors.initials: CR
authors.lastname: Wolf
authors.forename: C J
authors.initials: CJ
authors.lastname: Henderson
authors.forename: Z
authors.initials: Z
authors.lastname: Ronai
authors.forename: K D
authors.initials: KD
authors.lastname: Tew
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014162:Transfection
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; C096329:gamma-Glu-S-BzCys-PhGly diethyl ester; D013481:Superoxides; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C496557:Gstp1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione