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MAPK/ERK overrides the apoptotic signaling from Fas, TNF, and TRAIL receptors
S E Tran1, T H Holmstrom, M Ahonen
1Turku Centre for Biotechnology, POB 123, FIN-20521, University of Turku, Turku, Finland.
Abstract:
The tumor necrosis factor (TNF), Fas, and TNF-related apoptosis-inducing ligand (TRAIL) receptors (R) are highly specific physiological mediators of apoptotic signaling. We observed earlier that a number of FasR-insensitive cell lines could redirect the proapoptotic signal to an anti-apoptotic ERK1/2 signal resulting in inhibition of caspase activation. Here we determine that similar mechanisms are operational in regulating the apoptotic signaling of other death receptors. Activation of the FasR, TNF-R1, and TRAIL-R, respectively, rapidly induced subsequent ERK1/2 activation, an event independent from caspase activity. Whereas inhibition of the death receptor-mediated ERK1/2 activation was sufficient to sensitize the cells to apoptotic signaling from FasR and TRAIL-R, cells were still protected from apoptotic TNF-R1 signaling. The latter seemed to be due to the strong activation of the anti-apoptotic factor NF-kappaB, which remained inactive in FasR or TRAIL-R signaling. However, when the cells were sensitized with cycloheximide, which is sufficient to sensitize the cells also to apoptosis by TNF-R1 stimulation, we noticed that adenovirus-mediated expression of constitutively active MKK1 could rescue the cells from apoptosis induced by the respective receptors by preventing caspase-8 activation. Taken together, our results show that ERK1/2 has a dominant protecting effect over apoptotic signaling from the death receptors. This protection, which is independent of newly synthesized proteins, acts in all cases by suppressing activation of the caspase effector machinery.
Insights
The extracellular signal-regulated kinase 1/2 (ERK1/2) pathway protects cells from death receptor-induced apoptosis. This protective effect, independent of new protein synthesis, suppresses caspase activation across multiple death receptor pathways.
Area of Science:
- Cell Biology
- Molecular Biology
- Immunology
Background:
- Death receptors like Fas, TNF-R1, and TRAIL-R mediate apoptosis.
- Some cell lines resist Fas-induced apoptosis by activating ERK1/2.
- This study investigates if ERK1/2 also regulates other death receptor pathways.
Purpose of the Study:
- To determine if ERK1/2 activation is a common mechanism for other death receptors.
- To investigate the role of ERK1/2 in sensitizing cells to apoptosis.
- To explore the interplay between ERK1/2, NF-kappaB, and apoptosis.
Main Methods:
- Stimulation of FasR, TNF-R1, and TRAIL-R in cell lines.
- Inhibition of ERK1/2 activation and caspase activity.
- Sensitization of cells using cycloheximide.
- Adenovirus-mediated expression of MKK1.
Main Results:
- FasR, TNF-R1, and TRAIL-R activation induced ERK1/2, independent of caspases.
- Inhibiting ERK1/2 sensitized cells to FasR and TRAIL-R, but not TNF-R1 apoptosis.
- TNF-R1 resistance was linked to NF-kappaB activation.
- MKK1 expression rescued cells from receptor-induced apoptosis by preventing caspase-8 activation.
Conclusions:
- ERK1/2 activation is a dominant protective mechanism against death receptor-mediated apoptosis.
- This protection is independent of new protein synthesis and suppresses caspase activation.
- The findings highlight a conserved pathway regulating cell death signaling.