Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genomic instability is a hallmark of human cancers. Spindle assembly checkpoint (SAC) is a critical cellular mechanism that prevents chromosome missegregation and therefore aneuploidy by blocking premature separation of sister chromatids. Thus, SAC, much like the DNA damage checkpoint, is essential for genome stability. In this study, we report the generation and analysis of mice carrying a Cdc20 allele in which three residues critical for the interaction with Mad2 were mutated to alanine. The mutant Cdc20 protein (AAA-Cdc20) is no longer inhibited by Mad2 in response to SAC activation, leading to the dysfunction of SAC and aneuploidy. The dysfunction could not be rescued by the additional expression of another Cdc20 inhibitor, BubR1. Furthermore, we found that Cdc20(AAA/AAA) mice died at late gestation, but Cdc20(+/AAA) mice were viable. Importantly, Cdc20(+/AAA) mice developed spontaneous tumors at highly accelerated rates, indicating that the SAC-mediated inhibition of Cdc20 is an important tumor-suppressing mechanism.
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PMID:Loss of spindle assembly checkpoint-mediated inhibition of Cdc20 promotes tumorigenesis in mice. 1952 93

The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20. When the checkpoint signal is turned off, MCC is disassembled and the checkpoint is inactivated. The mechanisms of the disassembly of MCC are not sufficiently understood. We have previously observed that ATP hydrolysis is required for the action of the Mad2-binding protein p31(comet) to disassemble MCC. We now show that HeLa cell extracts contain a factor that promotes ATP- and p31(comet)-dependent disassembly of a Cdc20-Mad2 subcomplex and identify it as Thyroid Receptor Interacting Protein 13 (TRIP13), an AAA-ATPase known to interact with p31(comet). The joint action of TRIP13 and p31(comet) also promotes the release of Mad2 from MCC, participates in the complete disassembly of MCC and abrogates checkpoint inhibition of APC/C. We propose that TRIP13 plays centrally important roles in the sequence of events leading to MCC disassembly and checkpoint inactivation.
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PMID:Disassembly of mitotic checkpoint complexes by the joint action of the AAA-ATPase TRIP13 and p31(comet). 2509 94

During meiotic and mitotic cell divisions, numerous chromosomal processes are essential for the faithful transmission of the genetic material. Pch2(TRIP13), a generally conserved member of the AAA(+) ATPase (AAA(+)--ATPases associated with diverse cellular activities) family of ATPases, is rapidly emerging as a key regulator of specific chromosomal events. During the meiotic program, it is involved in controlling G2/prophase processes such as DNA break formation and recombination, checkpoint signaling, and chromosome synapsis. Excitingly, recent work has also implicated a role for Pch2(TRIP13) in wiring of the checkpoint that guards the metaphase-to-anaphase transition. For several of these functions, the Hop1, Rev7, and Mad2 (HORMA) domain-containing proteins Hop1(HORMAD), Mad2, and p31(COMET) are important downstream clients or cofactors of Pch2(TRIP13). Here, I will discuss our current understanding of the function of Pch2(TRIP13) during meiotic and mitotic cell divisions, with a focus on its enzymatic role towards HORMA domain-containing clients.
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PMID:Pch2(TRIP13): controlling cell division through regulation of HORMA domains. 2589 24

The AAA-ATPase thyroid hormone receptor interacting protein 13 (TRIP13), jointly with the Mad2-binding protein p31(comet), promotes the inactivation of the mitotic (spindle assembly) checkpoint by disassembling the mitotic checkpoint complex (MCC). This checkpoint system ensures the accuracy of chromosome segregation by delaying anaphase until correct bipolar attachment of chromatids to the mitotic spindle is achieved. MCC inhibits the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that targets for degradation securin, an inhibitor of anaphase initiation. MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3, in association with the APC/C activator Cdc20. The assembly of MCC in active checkpoint is initiated by the conversion of Mad2 from an open (O-Mad2) to a closed (C-Mad2) conformation, which then binds tightly to Cdc20. Conversely, the disassembly of MCC that takes place when the checkpoint is turned off involves the conversion of C-Mad2 back to O-Mad2. Previously, we found that the latter process is mediated by TRIP13 together with p31(comet), but the mode of their interaction remained unknown. Here, we report that the oligomeric form of TRIP13 binds both p31(comet) and MCC. Furthermore, p31(comet) and checkpoint complexes mutually promote the binding of each other to oligomeric TRIP13. We propose that p31(comet) bound to C-Mad2-containing checkpoint complex is the substrate for the ATPase and that the substrate-binding site of TRIP13 is composed of subsites specific for p31(comet) and C-Mad2-containing complex. The simultaneous occupancy of both subsites is required for high-affinity binding to TRIP13.
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PMID:Mode of interaction of TRIP13 AAA-ATPase with the Mad2-binding protein p31comet and with mitotic checkpoint complexes. 2632 90

The mitotic checkpoint system prevents premature separation of sister chromatids in mitosis and thus ensures the fidelity of chromosome segregation. When this checkpoint is active, a mitotic checkpoint complex (MCC), composed of the checkpoint proteins Mad2, BubR1, Bub3, and Cdc20, is assembled. MCC inhibits the ubiquitin ligase anaphase promoting complex/cyclosome (APC/C), whose action is necessary for anaphase initiation. When the checkpoint signal is turned off, MCC is disassembled, a process required for exit from checkpoint-arrested state. Different moieties of MCC are disassembled by different ATP-requiring processes. Previous work showed that Mad2 is released from MCC by the joint action of the TRIP13 AAA-ATPase and the Mad2-binding protein p31comet Now we have isolated from extracts of HeLa cells an ATP-dependent factor that releases Cdc20 from MCC and identified it as chaperonin containing TCP1 or TCP1-Ring complex (CCT/TRiC chaperonin), a complex known to function in protein folding. Bacterially expressed CCT5 chaperonin subunits, which form biologically active homooligomers [Sergeeva, et al. (2013) J Biol Chem 288(24):17734-17744], also promote the disassembly of MCC. CCT chaperonin further binds and disassembles subcomplexes of MCC that lack Mad2. Thus, the combined action of CCT chaperonin with that of TRIP13 ATPase promotes the complete disassembly of MCC, necessary for the inactivation of the mitotic checkpoint.
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PMID:Role of CCT chaperonin in the disassembly of mitotic checkpoint complexes. 2809 34

Spindle checkpoint strength is dictated by the number of unattached kinetochores, cell volume, and cell fate. We show that the conserved AAA-ATPase PCH-2/TRIP13, which remodels the checkpoint effector Mad2 from an active conformation to an inactive one, controls checkpoint strength in Caenorhabditis elegans. Having previously established that this function is required for spindle checkpoint activation, we demonstrate that in cells genetically manipulated to decrease in cell volume, PCH-2 is no longer required for the spindle checkpoint or recruitment of Mad2 at unattached kinetochores. This role is not limited to large cells: the stronger checkpoint in germline precursor cells also depends on PCH-2. PCH-2 is enriched in germline precursor cells, and this enrichment relies on conserved factors that induce asymmetry in the early embryo. Finally, the stronger checkpoint in germline precursor cells is regulated by CMT-1, the ortholog of p31comet, which is required for both PCH-2's localization to unattached kinetochores and its enrichment in germline precursor cells. Thus, PCH-2, likely by regulating the availability of inactive Mad2 at and near unattached kinetochores, governs checkpoint strength. This requirement may be particularly relevant in oocytes and early embryos enlarged for developmental competence, cells that divide in syncytial tissues, and immortal germline cells.
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PMID:The conserved AAA-ATPase PCH-2 TRIP13 regulates spindle checkpoint strength. 3269 29