Journal
DEVELOPMENTAL CELL
Volume 13, Issue 1, Pages 29-42Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2007.04.017
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Funding
- NCI NIH HHS [T32 CA09302-27] Funding Source: Medline
- NIGMS NIH HHS [R01 GM60439, R01 GM54811, R37 GM040198, GM07365] Funding Source: Medline
- PHS HHS [GMS 40198] Funding Source: Medline
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Cyclin-dependent kinase 1 (Cdk1) initiates mitosis and later activates the anaphase-promoting complex/cyclosome (APC/C) to destroy cyclins. Kinetochore-derived checkpoint signaling delays APC/C-dependent cyclin B destruction, and checkpoint-independent mechanisms cooperate to limit APC/C activity when kinetochores lack checkpoint components in early mitosis. The APC/C and cyclin B localize to the spindle and poles, but the significance and regulation of these populations remain unclear. Here we describe a critical spindle pole-associated mechanism, called the END (Emi1/ NuMA/dynein-dynactin) network, that spatially restricts APC/C activity in early mitosis. The APC/C inhibitor Emi1 binds the spindle-organizing NuMA/dynein-dynactin complex to anchor and inhibit the APC/C at spindle poles, and thereby limits destruction of spindle-associated cyclin B. Cyclin B/Cdk1 activity recruits the END network and establishes a positive feedback loop to stabilize spindle-associated cyclin B critical for spindle assembly. The organization of the APC/C on the spindle also provides a framework for understanding microtubule-dependent organization of protein destruction.
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