Caffeine Promotes Apoptosis in Mitotic Spindle Checkpoint-arrested Cells
| Autor: | Heather Beamish, Nichole Giles, Brian Gabrielli, Angus Harding, Yu-Qian Chau, Frankie Stevens |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
G2 Phase
Mad2 Cell cycle checkpoint Kinetochore Mitosis Apoptosis Spindle Apparatus Cell Biology Protein Serine-Threonine Kinases Biology G2-M DNA damage checkpoint Mitotic spindle checkpoint Biochemistry Cell Line Cell biology Spindle checkpoint p21-Activated Kinases Mitotic exit Caffeine Benzamides Quinazolines Humans biological phenomena cell phenomena and immunity Anaphase-promoting complex Molecular Biology |
| Zdroj: | Journal of Biological Chemistry. 282:6954-6964 |
| ISSN: | 0021-9258 |
| Popis: | The spindle assembly checkpoint arrests cells in mitosis when defects in mitotic spindle assembly or partitioning of the replicated genome are detected. This checkpoint blocks exit from mitosis until the defect is rectified or the cell initiates apoptosis. In this study we have used caffeine to identify components of the mechanism that signals apoptosis in mitotic checkpoint-arrested cells. Addition of caffeine to spindle checkpoint-arrested cells induced >40% apoptosis within 5 h. It also caused proteasome-mediated destruction of cyclin B1, a corresponding reduction in cyclin B1/cdk1 activity, and reduction in MPM-2 reactivity. However, cells retained MAD2 staining at the kinetochores, an indication of continued spindle checkpoint function. Blocking proteasome activity did not block apoptosis, but continued spindle checkpoint function was essential for apoptosis. After systematically eliminating all known targets, we have identified p21-activated kinase PAK1, which has an anti-apoptotic function in spindle checkpoint-arrested cells, as a target for caffeine inhibition. Knockdown of PAK1 also increased apoptosis in spindle checkpoint-arrested cells. This study demonstrates that the spindle checkpoint not only regulates mitotic exit but apoptosis in mitosis through the activity of PAK1. |
| Databáze: | OpenAIRE |
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