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The small GTPase Cdc42 initiates an apoptotic signaling pathway in Jurkat T lymphocytes
T H Chuang1, K M Hahn, J D Lee
1Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA.
Abstract:
Apoptosis plays an important role in regulating development and homeostasis of the immune system, yet the elements of the signaling pathways that control cell death have not been well defined. When expressed in Jurkat T cells, an activated form of the small GTPase Cdc42 induces cell death exhibiting the characteristics of apoptosis. The death response induced by Cdc42 is mediated by activation of a protein kinase cascade leading to stimulation of c-Jun amino terminal kinase (JNK). Apoptosis initiated by Cdc42 is inhibited by dominant negative components of the JNK cascade and by reagents that block activity of the ICE protease (caspase) family, suggesting that stimulation of the JNK kinase cascade can lead to caspase activation. The sequence of morphological events observed typically in apoptotic cells is modified in the presence of activated Cdc42, suggesting that this GTPase may account for some aspects of cytoskeletal regulation during the apoptotic program. These data suggest a means through which the biochemical and morphological events occurring during apoptosis may be coordinately regulated.
Insights
Activated Cdc42 GTPase triggers apoptosis in T cells by activating the JNK kinase cascade, leading to caspase activation and altered cell morphology. This suggests Cdc42 coordinates apoptosis signaling and cytoskeletal changes.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Apoptosis is crucial for immune system regulation, but its signaling pathways are not fully understood.
- The small GTPase Cdc42's role in apoptosis is under investigation.
Purpose of the Study:
- To investigate the role of activated Cdc42 in T cell apoptosis.
- To elucidate the signaling pathways involved in Cdc42-induced apoptosis.
Main Methods:
- Expression of activated Cdc42 in Jurkat T cells.
- Analysis of protein kinase cascades, including c-Jun amino terminal kinase (JNK).
- Inhibition studies using dominant-negative JNK components and caspase inhibitors.
Main Results:
- Activated Cdc42 induces apoptosis in T cells.
- Cdc42-induced apoptosis involves JNK kinase cascade activation.
- Apoptosis is inhibited by blocking JNK or caspase activity, indicating a link between JNK and caspases.
- Cdc42 alters the typical morphological events of apoptosis, suggesting cytoskeletal regulation.
Conclusions:
- Activated Cdc42 initiates apoptosis through the JNK pathway, leading to caspase activation.
- Cdc42 plays a role in coordinating the biochemical and morphological aspects of apoptosis, potentially through cytoskeletal regulation.