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The END network couples spindle pole assembly to inhibition of the anaphase-promoting complex/cyclosome in early mitosis.

Developmental cell | Jul 4, 2007

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.

Pubmed ID: 17609108 RIS Download

Mesh terms: Anaphase | Anaphase-Promoting Complex-Cyclosome | Antigens, Nuclear | CDC2 Protein Kinase | Cell Cycle Proteins | Chromosomes, Human | Cyclin B | Dynactin Complex | Dyneins | F-Box Proteins | Feedback, Physiological | HCT116 Cells | HeLa Cells | Humans | Microtubule-Associated Proteins | Nuclear Matrix-Associated Proteins | Protein Binding | Spindle Apparatus | Ubiquitin-Protein Ligase Complexes

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Associated grants

  • Agency: NCI NIH HHS, Id: T32 CA09302-27
  • Agency: NIGMS NIH HHS, Id: GM07365
  • Agency: PHS HHS, Id: GMS 40198
  • Agency: NIGMS NIH HHS, Id: R37 GM040198
  • Agency: NIGMS NIH HHS, Id: R01 GM54811
  • Agency: NIGMS NIH HHS, Id: R01 GM60439

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