title: Thyroid hormone receptor interacting protein 13 (TRIP13) AAA-ATPase is a novel mitotic checkpoint-silencing protein.
abstract: The mitotic checkpoint (or spindle assembly checkpoint) is a fail-safe mechanism to prevent chromosome missegregation by delaying anaphase onset in the presence of defective kinetochore-microtubule attachment. The target of the checkpoint is the E3 ubiquitin ligase anaphase-promoting complex/cyclosome. Once all chromosomes are properly attached and bioriented at the metaphase plate, the checkpoint needs to be silenced. Previously, we and others have reported that TRIP13 AAA-ATPase binds to the mitotic checkpoint-silencing protein p31(comet). Here we show that endogenous TRIP13 localizes to kinetochores. TRIP13 knockdown delays metaphase-to-anaphase transition. The delay is caused by prolonged presence of the effector for the checkpoint, the mitotic checkpoint complex, and its association and inhibition of the anaphase-promoting complex/cyclosome. These results suggest that TRIP13 is a novel mitotic checkpoint-silencing protein. The ATPase activity of TRIP13 is essential for its checkpoint function, and interference with TRIP13 abolished p31(comet)-mediated mitotic checkpoint silencing. TRIP13 overexpression is a hallmark of cancer cells showing chromosomal instability, particularly in certain breast cancers with poor prognosis. We suggest that premature mitotic checkpoint silencing triggered by TRIP13 overexpression may promote cancer development.
authors.affiliation: From the Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606.
authors.forename: Kexi
authors.initials: K
authors.lastname: Wang
authors.affiliation: From the Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606.
authors.forename: Brianne
authors.initials: B
authors.lastname: Sturt-Gillespie
authors.affiliation: the Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, and.
authors.forename: James C
authors.initials: JC
authors.lastname: Hittle
authors.affiliation: the Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada.
authors.forename: Dawn
authors.initials: D
authors.lastname: Macdonald
authors.affiliation: the Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada.
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Chan
authors.affiliation: the Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, and.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Yen
authors.affiliation: From the Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606, sliu@utnet.utoledo.edu.
authors.forename: Song-Tao
authors.initials: ST
authors.lastname: Liu
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D064246:Mad2 Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008938:Mitosis / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism; D034622:RNA Interference
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C501384:MAD1L1 protein, human; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D009687:Nuclear Proteins; D000074183:ATPases Associated with Diverse Cellular Activities; C575259:TRIP13 protein, human
keywords: ATPases Associated with Diverse Cellular Activities (AAA); Anaphase-promoting Complex/Cyclosome (APC/C),; Checkpoint Control; E3 Ubiquitin Ligase; MAD2; Mitosis; Mitotic Checkpoint Complex (MCC); Protein Complex; TRIP13; p31comet