The transforming growth factor beta(1)-inducible transcription factor, TIEG1, mediates apoptosis through oxidative stress

Transforming growth factor beta(1) (TGF-beta(1))-inducible transcription fa ctors have recently elicited interest because of their critical role in the regulation of cell proliferation, differentiation, and apoptosis. We have previously reported that the TGF-beta(1)-inducible transcription factor, TI EG1, induces apoptosis in a pancreas-derived cell Line. However, the mechan isms underlying the apoptotic effects of this transcription factor remain t o be defined. In this study, using the TGF-beta(1)-sensitive Hep 3B cell li ne, we have defined the mechanistic sequence of events that characterize TI EG1-mediated apoptosis and compared these events with the changes observed during TGF-beta(1)-induced apoptosis. Both TGF-beta(1)- and TIEG1-induced c ell death were accompanied by an increase in the generation of reactive oxy gen species and a loss of the mitochondrial membrane potential preceding th e morphological changes of apoptosis. In contrast, increases in caspase 3-l ike activity and glutathione (GSH) depletion occurred later in the apoptoti c process, concurrent with the morphological features of apoptosis. The ant ioxidant, trolox, decreased the formation of reactive oxygen species and ap optosis. These results demonstrate that similar to TGF-beta(1), TTEGI induc es apoptosis by a mechanism involving the formation of reactive oxygen spec ies.