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

Glutathione S-transferase P1-1 (GST pi) is an abundant and ubiquitously exp ressed protein in normal and malignant mammalian tissues and possesses cata lytic and ligand binding properties. Our present data suggest that the prot ein contributes to the regulation of cell proliferation. Mouse embryo fibro blasts (MEFs) isolated from mice with a GSTP1-1 [glutathione S-transferase P1-1 (isozyme in nonhepatic tissue)] null genotype (GST pi (-/-)) doubled t heir population in 26.2 h versus 33.6 h for the wild type (GST pi (+/+)). R etroviral transfection of GSTP1-1 into GST pi (-/-) MEF cells slowed the do ubling time to 30.4 h. Both early passage and immortalized MEF cells from G ST pi (-/-) animals expressed significantly elevated activity of extracellu lar signal-regulated kinases ERK1/ERK2, kinases linked to cell proliferatio n pathways. in vivo, GST pi (-/-) mice had higher basal levels of circulati ng white blood cells compared with GST pi (+/+). Administration of a peptid omimetic 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) prolif eration, but only in GST pi (+/+) and not in GST pi (-/-) animals. Selectio n 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 str ess 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 GSTP 1-1 influences cell proliferation.