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MST1-JNK promotes apoptosis via caspase-dependent and independent pathways
S Ura1, N Masuyama, J D Graves
1Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Background:
MST1 is an upstream kinase of the JNK and p38 MAPK pathways whose expression induces apoptotic morphological changes such as nuclear condensation. During apoptosis, caspase cleavage of MST1 removes a C-terminal regulatory domain, increasing the kinase activity of the MST1 N-terminal domain. Downstream pathways of MST1 in the induction of apoptosis remain to be clarified.
Results:
In this study, we found that the expression of MST1 resulted in caspase-3 activation. Therefore, MST1 is not only a target of caspases but also an activator of caspases. This caspase activation and apoptotic changes occur through JNK, since the co-expression of a dominant-negative mutant of JNK inhibited MST1-induced morphological changes as well as caspase activation. In contrast, neither a dominant-negative p38 nor the p38 inhibitor SB203580 inhibited them. MST1 induced nucleosomal DNA fragmentation, which was suppressed by caspase inhibitors or ICAD (Inhibitor of Caspase-Activated DNase). Surprisingly, however, other changes such as membrane blebbing and chromatin condensation were not inhibited by caspase inhibitors.
Conclusion:
These results suggest that MST1 most likely promotes two events through JNK activation; first, MST1 induces the activation of caspases, resulting in CAD-mediated DNA fragmentation, and second, MST1 induces chromatin condensation and membrane blebbing without utilizing downstream caspases.
Insights
Mammalian sterile 20-like kinase 1 (MST1) activates caspases and induces apoptosis through JNK signaling. MST1 triggers DNA fragmentation via caspases and also causes chromatin condensation and membrane blebbing independently of caspases.
Area of Science:
- Cell Biology
- Molecular Biology
- Apoptosis Signaling
Background:
- Mammalian sterile 20-like kinase 1 (MST1) is an upstream kinase regulating JNK and p38 MAPK pathways.
- MST1 expression induces apoptotic morphological changes, including nuclear condensation.
- Caspase cleavage of MST1 enhances its kinase activity, but downstream pathways remain unclear.
Purpose of the Study:
- To elucidate the downstream signaling pathways of MST1 in apoptosis induction.
- To investigate the role of MST1 in caspase activation and apoptotic morphological changes.
Main Methods:
- Co-expression of MST1 with dominant-negative JNK or p38 mutants.
- Treatment with p38 inhibitor SB203580.
- Assessment of caspase activation, morphological changes, and DNA fragmentation.
- Use of caspase inhibitors and ICAD.
Main Results:
- MST1 expression activated caspase-3, indicating a dual role as both target and activator.
- JNK signaling mediated MST1-induced caspase activation and morphological changes.
- MST1 induced nucleosomal DNA fragmentation, suppressed by caspase inhibitors.
- MST1-induced membrane blebbing and chromatin condensation were independent of caspase activity.
Conclusions:
- MST1 promotes JNK-dependent caspase activation, leading to DNA fragmentation.
- MST1 also induces caspase-independent chromatin condensation and membrane blebbing.