THESIS
2021
1 online resource (195 pages) : illustrations (some color)
Abstract
Anti-mitotic drugs block cells in mitosis and trigger mitotic cell death. Chemotherapeutic drugs
can fail, however, if cells undergo mitotic slippage. Understanding of molecular mechanism of
mitotic cell fate can improve strategies targeting mitosis for anti-cancer therapy. A threshold
model has been used to explain why cells undergo mitotic cell death or mitotic slippage, which
is, however, too simplistic a view. Here this study demonstrates that anti-apoptotic protein
MCL1, which is degraded rapidly in mitosis, is involved in setting the threshold of mitotic cell
death during early stages of mitotic arrest. Degradation of MCL1 is independent on the mitotic
ubiquitin ligase APC/C
CDC20 or SCF complex, which have been reported to regulate MCL-1
degradation during interphase. Basal level...[
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Anti-mitotic drugs block cells in mitosis and trigger mitotic cell death. Chemotherapeutic drugs
can fail, however, if cells undergo mitotic slippage. Understanding of molecular mechanism of
mitotic cell fate can improve strategies targeting mitosis for anti-cancer therapy. A threshold
model has been used to explain why cells undergo mitotic cell death or mitotic slippage, which
is, however, too simplistic a view. Here this study demonstrates that anti-apoptotic protein
MCL1, which is degraded rapidly in mitosis, is involved in setting the threshold of mitotic cell
death during early stages of mitotic arrest. Degradation of MCL1 is independent on the mitotic
ubiquitin ligase APC/C
CDC20 or SCF complex, which have been reported to regulate MCL-1
degradation during interphase. Basal level of MCL1 in mitosis is regulated by ubiquitin ligase
MARCH5, whose depletion induces mitotic cell death even with stabilized MCL1. MARCH5
depletion mediates mitotic cell death in MCL1-dependent or independent manner. MARCH5
regulates mitotic cell death through BAK. Degradation of cyclin B1 is believed to determine
the threshold of mitotic slippage. This study shows that mitotic slippage involves reduction of
MAD2 at the kinetochores, resulting in a progressive weakening of spindle-assembly
checkpoint (SAC) during mitotic arrest. Inhibition of APC/C
CDC20 reduces the loss of
kinetochore MAD2, which indicates a feedback control of APC/C
CDC20 to SAC. SAC
weakening enables APC/C
CDC20 to ubiquitinate cyclin B1, leading to cyclin B1 degradation and
mitotic slippage. These results highlight the multiple factors controlling the fate of mitotic
arrested cells.
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