Elevated glutathione S-transferase gene expression is an early event during steroid-induced lymphocyte apoptosis.
Based on the finding that glutathione S-transferase Yb1 (GST) gene expression is elevated in the regressing prostate of androgen-ablated rats, we analyzed GST transcript levels during steroid-induced lymphocyte cell death. It was found that GST gene expression was induced in steroid-sensitive cells within 4 hr of dexamethasone treatment, required functional glucocorticoid receptor, and was dose-dependent with regard to hormone. GST expression was not induced in an apoptosis-defective variant that contained normal levels of functional receptor, indicating that GST up-regulation was the result of secondary events that occur during steroid-mediated apoptosis. Using the calcium ionophore A23817 to induce lymphocyte cell death, GST RNA levels were increased in both steroid-sensitive and steroid-resistant cell lines, supporting the conclusion that elevated GST expression was the result of cellular processes associated with apoptosis, rather than a direct consequence of steroid-mediated transcriptional control. The cells were also treated with dibutyryl cAMP to cause cell death; however, this mode of killing did not result in GST up-regulation. Taken together, these results suggest that GST induction in dexamethasone-treated T-lymphocytes occurs early in the steroid-regulated apoptotic pathway and that this may be a marker of calcium-stimulated cell death. Based on the known function of GST as an antioxidant defense enzyme and its transcriptional regulation by reactive oxygen intermediates, we propose that the gene product of a primary GR target gene(s) directly or indirectly effects the redox state of the cell. Thus activation of GST gene expression in apoptotic lymphocytes is likely a indicator of oxidative stress, rather than a required step in the pathway.
Flomerfelt
F A
FA
Department of Molecular and Cellular Biology, University of Arizona, Tucson 85724.
Briehl
M M
MM
Dowd
D R
DR
Dieken
E S
ES
Miesfeld
R L
RL
D000818:Animals; D017209:Apoptosis; D003994:Bucladesine / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D004790:Enzyme Induction; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D000001:Calcimycin; D003994:Bucladesine; D003907:Dexamethasone; D005982:Glutathione Transferase