title: Homeostatic control of mitotic arrest.
abstract: The spindle assembly checkpoint (SAC) restricts mitotic exit to cells that have completed chromosome-microtubule attachment. Cdc20 is a bifunctional protein. In complex with SAC proteins Mad2, BubR1, and Bub3, Cdc20 forms the mitotic checkpoint complex (MCC), which binds the anaphase-promoting complex (APC/C) and inhibits its mitotic exit-promoting activity. When devoid of SAC proteins, Cdc20 serves as an APC/C coactivator and promotes mitotic exit. During mitotic arrest, Cdc20 is continuously degraded via ubiquitin-dependent proteolysis and resynthesized. It is believed that this cycle keeps the levels of Cdc20 below a threshold above which Cdc20 would promote mitotic exit. We report that p31(comet), a checkpoint antagonist, is necessary for mitotic destabilization of Cdc20. p31(comet) depletion stabilizes the MCC, super-inhibits the APC/C, and delays mitotic exit, indicating that Cdc20 proteolysis in prometaphase opposes the checkpoint. Our studies reveal a homeostatic network in which checkpoint-sustaining and -repressing forces oppose each other during mitotic arrest and suggest ways for enhancing the sensitivity of cancer cells to antitubulin chemotherapeutics.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology Via Adamello 16, 20139 Milan, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Varetti
authors.forename: Claudia
authors.initials: C
authors.lastname: Guida
authors.forename: Stefano
authors.initials: S
authors.lastname: Santaguida
authors.forename: Elena
authors.initials: E
authors.lastname: Chiroli
authors.forename: Andrea
authors.initials: A
authors.lastname: Musacchio
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D064173:Anaphase-Promoting Complex-Cyclosome; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D006367:HeLa Cells; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D015739:Nocodazole / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism; D049468:Prometaphase / Q000187:drug effects; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; C470309:MAD2L1BP protein, human; D009687:Nuclear Proteins; C577488:CDC20 protein, human; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D015739:Nocodazole