Transforming growth factor beta(1) (TGF-beta(1))-inducible transcription factors 
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, TIEG1, induces 
apoptosis in a pancreas-derived cell line. However, the mechanisms underlying 
the apoptotic effects of this transcription factor remain to be defined. In this 
study, using the TGF-beta(1)-sensitive Hep 3B cell line, we have defined the 
mechanistic sequence of events that characterize TIEG1-mediated apoptosis and 
compared these events with the changes observed during TGF-beta(1)-induced 
apoptosis. Both TGF-beta(1)- and TIEG1-induced cell death were accompanied by an 
increase in the generation of reactive oxygen species and a loss of the 
mitochondrial membrane potential preceding the morphological changes of 
apoptosis. In contrast, increases in caspase 3-like activity and glutathione 
(GSH) depletion occurred later in the apoptotic process, concurrent with the 
morphological features of apoptosis. The antioxidant, trolox, decreased the 
formation of reactive oxygen species and apoptosis. These results demonstrate 
that similar to TGF-beta(1), TIEG1 induces apoptosis by a mechanism involving 
the formation of reactive oxygen species.