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The transforming growth factor beta(1)-inducible transcription factor TIEG1, mediates apoptosis through oxidative
A Ribeiro1, S F Bronk, P J Roberts
1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA.
Abstract:
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.
Insights
Transforming growth factor beta(1) (TGF-beta(1)) and its TIEG1 protein induce cell death. Both pathways involve reactive oxygen species generation, a loss of mitochondrial membrane potential, and are reduced by the antioxidant trolox.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Transforming growth factor beta(1) (TGF-beta(1))-inducible transcription factors regulate crucial cellular processes.
- TIEG1, a TGF-beta(1)-inducible transcription factor, has been shown to induce apoptosis in pancreatic cells.
- The precise mechanisms of TIEG1-mediated apoptosis require further elucidation.
Purpose of the Study:
- To define the mechanistic sequence of events in TIEG1-mediated apoptosis.
- To compare TIEG1-induced apoptosis with TGF-beta(1)-induced apoptosis.
- To investigate the role of reactive oxygen species in TIEG1-induced apoptosis.
Main Methods:
- Utilized the TGF-beta(1)-sensitive Hep 3B cell line.
- Monitored reactive oxygen species generation and mitochondrial membrane potential.
- Assessed caspase 3-like activity, glutathione (GSH) levels, and morphological changes of apoptosis.
- Evaluated the effect of the antioxidant trolox.
Main Results:
- Both TGF-beta(1) and TIEG1 induced apoptosis with increased reactive oxygen species and loss of mitochondrial membrane potential.
- Caspase 3-like activity and GSH depletion occurred later in the apoptotic process.
- The antioxidant trolox attenuated reactive oxygen species formation and apoptosis.
Conclusions:
- TIEG1 induces apoptosis through a mechanism involving reactive oxygen species formation, similar to TGF-beta(1).
- Reactive oxygen species and mitochondrial dysfunction are early events in TIEG1-mediated apoptosis.
- Targeting reactive oxygen species may offer therapeutic strategies for TIEG1-related cellular processes.