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Smad7 inhibits the survival nuclear factor kappaB and potentiates apoptosis in epithelial cells
F Lallemand1, A Mazars, C Prunier
1INSERM U. 482, Hôpital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France.
Abstract:
In this study, we examined the effect of the stable expression of Smad7 in two different cell lines on apoptosis induced by various stimuli including TGF-beta, serum withdrawal, loss of cell adhesion (anoikis) and TNF-alpha. Smad7 increased TGF-beta-mediated apoptosis in Mv1Lu cells as well as anoikis and/or serum withdrawal-induced apoptosis in Mv1Lu and MDCK cells. Smad7 markedly decreased the activity of the survival NF-kappaB transcription factor in MDCK cells. Interestingly, the stable expression of oncogenic Ras in MDCK cells which suppressed Smad7 inhibition of NF-kappaB also suppressed Smad7 potentiation of serum withdrawal-induced apoptosis and anoikis. In addition, Smad7 inhibited TNF-alpha stimulation of NF-kappaB and increased TNF-alpha-mediated apoptosis in MDCK cells. Our results provide the first evidence that Smad7 induces sensitization of cells to different forms of cell death. They moreover demonstrate that Smad7 inhibits the survival NF-kappaB factor, providing a potential mechanism whereby Smad7 potentiates cell death.
Insights
Smad7 enhances cell death pathways, including apoptosis and anoikis, by inhibiting the survival factor NF-kappaB. This study reveals Smad7
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Smad7 is a known inhibitor of transforming growth factor-beta (TGF-β) signaling.
- The role of Smad7 in regulating apoptosis induced by various stimuli is not fully understood.
- NF-kappaB is a key transcription factor involved in cell survival pathways.
Purpose of the Study:
- To investigate the effect of stable Smad7 expression on apoptosis induced by TGF-β, serum withdrawal, anoikis, and TNF-α.
- To elucidate the mechanism by which Smad7 influences apoptosis, particularly its interaction with NF-κB signaling.
Main Methods:
- Stable expression of Smad7 in Mv1Lu and MDCK cell lines.
- Induction of apoptosis using TGF-β, serum withdrawal, anoikis, and TNF-α.
- Measurement of apoptosis and NF-κB transcription factor activity.
Main Results:
- Smad7 expression increased TGF-β-mediated apoptosis in Mv1Lu cells.
- Smad7 promoted apoptosis induced by anoikis and serum withdrawal in Mv1Lu and MDCK cells.
- Smad7 inhibited NF-κB activity and enhanced TNF-α-induced apoptosis in MDCK cells.
- Oncogenic Ras expression in MDCK cells suppressed Smad7's inhibition of NF-κB and its pro-apoptotic effects.
Conclusions:
- Smad7 sensitizes cells to various forms of cell death, including apoptosis and anoikis.
- Smad7 inhibits the survival transcription factor NF-κB, providing a mechanism for its pro-apoptotic function.
- These findings highlight Smad7 as a potential regulator of cell death and survival pathways.