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

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