FUNCTIONAL MODULATION OF ESTROGEN-RECEPTOR BY REDOX STATE WITH REFERENCE TO THIOREDOXIN AS A MEDIATOR

Redox regulation of transcription factors has recently been demonstrat ed for AP-1, NF-kappa B, Sp-1 and glucocorticoid receptor in vitro and in vivo. The redox state in estrogen-dependent cells possibly influen ces the function of estrogen receptor (ER), and the regulation of the function of ER is essential for understanding of growth and differenti ation of these cells, as well as promotion and progression of estrogen -associated cancer, In this paper, we first analyzed the effects of re dox state on transcriptional activity of ER in terms of pS2 mRNA expre ssion and transfection of ERE-CAT plasmid in human breast cancer cells . Addition of H2O2 at low concentrations lowered levels of pS2 mRNA an d also down-regulated ERE-CAT activity, which was recovered by transfe ction of thioredoxin (TRX) expression vector, Next, the transfection o f antisense TRX plasmid diminished ERE-CAT activity, and the activity was recovered by co-transfected sense TRX. Furthermore, specific DNA b inding activity of recombinant ER was inhibited by sulfhydryl-modifyin g reagents and restored by the addition of recombinant TRX protein in electrophoretic mobility shift assay. These results in vitro and in vi vo revealed that the transcription activity of ER is strongly influenc ed by its redox state, which is reversibly modulated by endogenous red ox effector protein, TRX.