Two different mitotic checkpoint inhibitors of the anaphase-promoting complex/cyclosome antagonize the action of the activator Cdc20

Eytan, Esther; Braunstein, Ilana; Ganoth, Dvora; Teichner, Adar; Hittle, James C.; Yen, Tim J.; Hershko, Avram

doi:10.1073/pnas.0804069105

Cited by 22 publications

(46 citation statements)

References 21 publications

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“…When such extracts were incubated in the presence of ATP, APC/C was converted to an active form following a lag period. This process was accompanied by the release of inhibitory factors from APC/C and the disassembly of MCC (8,9). We found that the hydrolysis of ATP at the β−γ position was required for both for the activation of APC/C and for the disassembly of MCC (10); this was different from the previously described requirement of checkpoint inactivation for ubiquitylation (11,12), because the latter process involves the cleavage of the α−β bond of ATP (13).…”

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confidence: 53%

Role of phosphorylation of Cdc20 in p31 ^comet -stimulated disassembly of the mitotic checkpoint complex

Miniowitz-Shemtov

Eytan

Ganoth

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The mitotic checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is turned on, it promotes the formation of the mitotic checkpoint complex (MCC), which inhibits the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C). MCC is composed of the checkpoint proteins BubR1, Bub3, and Mad2 bound to the APC/C activator Cdc20. When the checkpoint is satisfied, MCC is disassembled and APC/C becomes active. Previous studies have shown that the Mad2-binding protein p31 comet promotes the dissociation of Cdc20 from BubR1 in MCC in a process that requires ATP. We now show that a part of MCC dissociation is blocked by inhibitors of cyclin-dependent kinases (Cdks) and that purified Cdk1–cyclin B stimulates this process. The mutation of all eight potential Cdk phosphorylation sites of Cdc20 partially prevented its release from BubR1. Furthermore, p31 comet stimulated Cdk-catalyzed phosphorylation of Cdc20 in MCC. It is suggested that the binding of p31 comet to Mad2 in MCC may trigger a conformational change in Cdc20 that facilitates its phosphorylation by Cdk, and that the latter process may promote its dissociation from BubR1.

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confidence: 53%

Role of phosphorylation of Cdc20 in p31 ^comet -stimulated disassembly of the mitotic checkpoint complex

Miniowitz-Shemtov

Eytan

Ganoth

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The APC can be inhibited in multiple ways, and complexes of APC together with either Cdc20:C-Mad2, Bub3:BubR1, Bub3:BubR1:Cdc20, MCC, or MCF2 have been found to be inactive (Eytan et al, 2008;Herzog et al, 2009;Kulukian et al, 2009a;Malureanu et al, 2009;Medema, 2009;Sudakin et al, 2001). However, the demand mechanisms for binding the inhibitory complexes to the APC are subject to current research.…”

Section: Apc Inhibitionmentioning

confidence: 99%

“…The MCC may also bind to APC in a kinetochore independent manner to eventually inhibit APC by releasing O-Mad2, forming the stable Bub3:BubR1:Cdc20:APC complex. The recently discovered mitotic checkpoint factor 2 protein (MCF2) is a highly potent APC inhibitor, yet the mechanism of binding to the APC and its regulation is still elusive (Braunstein et al, 2007;Eytan et al, 2008). All complexes inhibiting APC (except of MCF2) rely on the presence of Cdc20:C-Mad2, which requires unattached kinetochores for adequately fast formation.…”

Section: Apc Inhibitionmentioning

confidence: 99%

“…2 · 10 -2 s -1 (Ibrahim et al 2008b, Ibrahim andHenze, 2014) ( Eytan et al 2008), this study Other species start from zero 296 IBRAHIM theoretical point of view (Ibrahim et al, 2008b).This loop was therefore not considered in the model. For integrity, the biochemical equations of the autocatalytic amplification are listed by reaction (R4)-(R5) (see chemical reaction scheme, below).…”

Section: Autocatalytic Amplification Of Cdc20:c-mad2 Formationmentioning

confidence: 99%

“…Furthermore, BubR1 was suggested to interact with APC/C (Han et al, 2013). Another inhibitor, called the mitotic checkpoint factor 2 (MCF2), is associated with APC merely in the checkpoint arrested state but its composition is not known (Eytan et al, 2008). With the exception of MCF2, all complexes inhibiting APC rely on the presence of Cdc20:C-Mad2, which requires unattached kinetochores for adequately fast formation.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Systems Biology Modeling of Five Pathways for Regulation and Potent Inhibition of the Anaphase-Promoting Complex (APC/C): Pivotal Roles for MCC and BubR1

Ibrahim

2015

OMICS: A Journal of Integrative Biology

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Correct DNA segregation is a fundamental process that ensures the precise and reliable inheritance of genomic information for the propagation of cell life. Eukaryotic cells have evolved a conserved surveillance control mechanism for DNA segregation named the Spindle Assembly Checkpoint (SAC).The SAC ensures that the sister chromatids of the duplicated genome are not separated and distributed to the spindle poles before all chromosomes have been properly linked to the microtubules of the mitotic spindle. Biochemically, the SAC delays cell cycle progression by preventing activation of the anaphase-promoting complex (APC/C) or cyclosome whose activation by Cdc20 is required for sister-chromatid separation; this marks the transition into anaphase. In response to activation of the checkpoint, various species control the activity of both APC/C and Cdc20. However, the underlying regulatory pathways remain largely elusive. In this study, five possible model variants of APC/C regulation were constructed, namely BubR1, Mad2, MCC, MCF2, and an all-pathways model variant. These models were validated with experimental data from the literature. A wide range of parameter values has been tested to find the critical values of the APC/C binding rate. The results show that all variants are able to capture the wild-type behavior of the APC/C. However, only one model variant, which included both MCC as well as BubR1 as potent inhibitors of the APC/C, was able to reproduce both wild-type and mutant type behavior of APC/C regulation. In conclusion, the presented work informs the regulation of fundamental processes such as SAC and APC/C in cell biology and has successfully distinguished between five competing dynamical models using a systems biology approach. The results attest that systems-level approaches are vital for molecular and cell biology.

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The influence of ADAR1’s regulation on lymphocyte cell function during rejection

Liu

Zhang

et al. 2009

Mol Biol Rep

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The RNA editing adenosine deaminase gene (ADAR1) expression is wide-spread in lymphocytes. We explore the mechanism of ADAR1 regulation on the function of T primary lymphocytes when rejection occurs by knock-down the expression of ADAR1 in mouse T primary lymphocytes in mixed lymphocyte cultures. The changes of cell proliferation, the expression of ADAR1 and the cell cycle related genes cyclin D1 and A1, cell cycle and apoptosis analysis and mouse gene expression profiles was evaluated. We found that treatment with ADAR1-specific siRNA inhibited allogenic antigen stimulated T cell proliferation, arrested T cell cycle at G(0)/G(1) phases and promoted T cell apoptosis, which was associated with down-regulation of some related key genes transcription. These findings suggest that ADAR1 is essential for the maintenance of function of T lymphocytes during acute rejection. The mechanism underlying ADAR1's action might include editing of a currently unknown substrate and interacting with other proteins.

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Two different mitotic checkpoint inhibitors of the anaphase-promoting complex/cyclosome antagonize the action of the activator Cdc20

Cited by 22 publications

References 21 publications

Role of phosphorylation of Cdc20 in p31 ^comet -stimulated disassembly of the mitotic checkpoint complex

Role of phosphorylation of Cdc20 in p31 ^comet -stimulated disassembly of the mitotic checkpoint complex

Systems Biology Modeling of Five Pathways for Regulation and Potent Inhibition of the Anaphase-Promoting Complex (APC/C): Pivotal Roles for MCC and BubR1

The influence of ADAR1’s regulation on lymphocyte cell function during rejection

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Two different mitotic checkpoint inhibitors of the anaphase-promoting complex/cyclosome antagonize the action of the activator Cdc20

Cited by 22 publications

References 21 publications

Role of phosphorylation of Cdc20 in p31 comet -stimulated disassembly of the mitotic checkpoint complex

Role of phosphorylation of Cdc20 in p31 comet -stimulated disassembly of the mitotic checkpoint complex

Systems Biology Modeling of Five Pathways for Regulation and Potent Inhibition of the Anaphase-Promoting Complex (APC/C): Pivotal Roles for MCC and BubR1

The influence of ADAR1’s regulation on lymphocyte cell function during rejection

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Role of phosphorylation of Cdc20 in p31 ^comet -stimulated disassembly of the mitotic checkpoint complex

Role of phosphorylation of Cdc20 in p31 ^comet -stimulated disassembly of the mitotic checkpoint complex