The transforming growth factor β1-inducible transcription factor, TIEG1, mediates apoptosis through oxidative stress

Abstract

Transforming growth factor ␤ 1 (TGF-␤ 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-␤ 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-␤ 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-␤ 1 -induced apoptosis. Both TGF-␤ 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-␤ 1 , TIEG1 induces apoptosis by a mechanism involving the formation of reactive oxygen species.

Kruppel-like Factor KLF10 Targets Transforming Growth Factor-β1 to Regulate CD4+CD25− T Cells and T Regulatory Cells

“…KLF10 was initially identified in human osteoblasts as a TGF-␤ responsive gene (31), and gene-targeting experiments in mice have verified a critical role for this factor in osteoblast-mediated mineralization and osteoblast support of osteoclast differentiation (32). In vitro studies have implicated KLF10 as either a transcriptional activator or suppressor depending on the cell line of examination (33)(34)(35) …”

Regulation of cell proliferation by Smad proteins

“…3) (Motyl et al, 1998;Francis et al, 2000;Chipuk et al, 2001;Kim et al, 2001). In addition, TGF-b-mediated induction of Id3 expression in primary B lymphocyte progenitors (Kee et al, 2001), TIEG in mink lung epithelial and Hep3B cells (Chalaux et al, 1999;Ribeiro et al, 1999), and TGFb-stimulated clone 22 (TSC-22) in gastric carcinoma cells (Ohta et al, 1997), have been implicated in apoptosis. However, whether Smads are directly regulating the expression of these genes with role in apoptosis is not known.…”

Characterization of the Transforming Growth Factor-β1-induced Apoptotic Transcriptome in FaO Hepatoma Cells

“…Significantly, the TGF-␤ 1 -inducible transcription factor TIEG1 (TGF-␤ 1 -inducible early response gene-1) also induces apoptosis via an increase in ROS and loss of mitochondrial ⌬ (67). TGF-␤ 1 -induced oxidative stress and apoptosis can be blocked in part by antioxidant treatment (66,67) and accentuated by inhibitors of glutathione synthesis (29). Glutathione is synthesized in a two-step reaction from glutamate and cysteine to form L-␥-glutamylcysteine, which is then conjugated with glycine to produce reduced glutathione (for review, see Ref.…”