Determinants of conformational dimerization of Mad2 and its inhibition by p31comet

Mapelli, Marina; Filipp, Fabian V.; Rancati, Giulia; Massimiliano, Lucia; Nezi, Luigi; Stier, Günter; Hagan, Robert S; Confalonieri, Stefano; Piatti, Simonetta; Sattler, Michael; Musacchio, Andrea

doi:10.1038/sj.emboj.7601033

Cited by 125 publications

(180 citation statements)

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“…In our analysis using untransformed human fibroblast cells, p31 comet overexpression led to immediate cell death rather than senescence. 9 These findings, together with our present results showing that p31 comet did not affect the level of BubR1 expression, indicate that p31 comet has a mechanism quite different from BubR1 in inducing senescence. Although the level of p53 protein was also significantly elevated together with p21, our data indicate that accumulation of p21 Waf1/Cip1 , but not p53, is a prerequisite for p31 comet -induced senescence (Figs.…”

Section: Discussionsupporting

confidence: 71%

“…It is proposed that p31 comet facilitates dissociation of Mad2 by transient interactions with the inhibitory Mad2-Cdc20-containing complexes to allow transition from the metaphase to anaphase during mitotic checkpoint inactivation. Other reports suggest that p31 comet enhances the activity of APC/C, which is otherwise inhibited by Mad2, without disrupting Mad2-Cdc20 binding in the transient Mad2-Cdc20-APC/C complex (8,9). Both hypotheses concur that p31 comet counteracts Mad2 function and is required for silencing the spindle checkpoint.…”

Section: Introductionsupporting

confidence: 65%

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p31comet Induces Cellular Senescence through p21 Accumulation and Mad2 Disruption

Yun

Han

Yoon

et al. 2009

Molecular Cancer Research

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Functional suppression of spindle checkpoint protein activity results in apoptotic cell death arising from mitotic failure, including defective spindle formation, chromosome missegregation, and premature mitotic exit. The recently identified p31 comet protein acts as a spindle checkpoint silencer via communication with the transient Mad2 complex. In the present study, we found that p31 comet overexpression led to two distinct phenotypic changes, cellular apoptosis and senescence. Because of a paucity of direct molecular link of spindle checkpoint to cellular senescence, however, the present report focuses on the relationship between abnormal spindle checkpoint formation and p31 comet -induced senescence by using susceptible tumor cell lines. p31 comet -induced senescence was accompanied by mitotic catastrophe with massive nuclear and chromosomal abnormalities. The progression of the senescence was completely inhibited by the depletion of p21 Waf1/Cip1 and partly inhibited by the depletion of the tumor suppressor protein p53. Notably, p21 Waf1/Cip1 depletion caused a dramatic phenotypic conversion of p31 comet -induced senescence into cell death through mitotic catastrophe, indicating that p21 Waf1/Cip1 is a major mediator of p31 comet -induced cellular senescence. In contrast to wild-type p31 comet , overexpression of a p31 mutant lacking the Mad2 binding region did not cause senescence. Moreover, depletion of Mad2 by small interfering RNA induced senescence. Here, we show that p31 comet induces tumor cell senescence by mediating p21 Waf1/Cip1 accumulation and Mad2 disruption and that these effects are dependent on a direct interaction of p31 comet with Mad2. Our results could be used to control tumor growth. (Mol Cancer Res 2009;7(3):371 -82)

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Section: Discussionsupporting

confidence: 71%

Section: Introductionsupporting

confidence: 65%

p31comet Induces Cellular Senescence through p21 Accumulation and Mad2 Disruption

Yun

Han

Yoon

et al. 2009

Molecular Cancer Research

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“…In this way, the relatively weak signal coming from an unattached kinetochore can be amplified, leading to comprehensive Cdc20 sequestration throughout the cell. Recent experiments have further implicated a protein called p31 comet in switching off this signal after complete kinetochore attachment (7,12,13). However, the above ''Mad template'' model is not the only proposed mechanism for APC͞C repression.…”

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confidence: 99%

Modeling dual pathways for the metazoan spindle assembly checkpoint

Sear

Howard

2006

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

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Using computational modeling, we investigate mechanisms of signal transduction. We focus on the spindle assembly checkpoint, where a single unattached kinetochore is able to signal to prevent cell cycle progression. The inhibitory signal switches off rapidly once spindle microtubules have attached to all kinetochores. This requirement tightly constrains the possible mechanisms. Here we investigate two possible mechanisms for spindle checkpoint operation in metazoan cells, both supported by recent experiments. The first involves the free diffusion and sequestration of cell cycle regulators. This mechanism is severely constrained both by experimental fluorescence recovery data and by the large volumes involved in open mitosis in metazoan cells. By using a simple mathematical analysis and computer simulation, we find that this mechanism can generate the inhibition found in experiment but likely requires a two-stage signal amplification cascade. The second mechanism involves spatial gradients of a short-lived inhibitory signal that propagates first by diffusion but then primarily by active transport along spindle microtubules. We propose that both mechanisms may be operative in the metazoan spindle assembly checkpoint, with either able to trigger anaphase onset even without support from the other pathway.kinetochore ͉ mathematical modeling ͉ signal transduction ͉ concentration gradients T he question of how a signal emanating from a small, compact structure in a cell can be amplified and propagated to an entire cell is fundamental to cell biology (1). An excellent example is provided by the spindle assembly checkpoint (SAC) (2), which regulates cell cycle progression from metaphase to anaphase during mitosis. The segregation of sister chromatids that occurs during anaphase is permitted only after all of the kinetochores are attached by microtubules to the mitotic spindle. Even a single unattached kinetochore can signal to the rest of the cell and prevent cell cycle progression (3, 4). A fundamental issue is how a relatively small structure, such as a kinetochore, can generate sufficient signal to robustly communicate with distant subcellular locations (1). Moreover, this signal must switch off rapidly, within a period of minutes, after complete kinetochore attachment to spindle microtubules (4). These requirements strongly constrain the possible signal transduction mechanisms. In this paper, we focus particularly on the SAC in cases where the nuclear envelope breaks down before SAC activity (open mitosis), as in metazoan cells. In this context, we examine two distinct models: a diffusive sequestration model and a model involving active signal transport along spindle microtubules. We believe that both of these pathways may be in simultaneous operation in the metazoan SAC.The metaphase͞anaphase transition is triggered by an intricate sequence of events centered around the proteins securin, cyclin B, and separase. The first step is the ubiquitination of securin and cyclin B by the anaphase-promoting complex͞cyclosome (...

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“…Finally, the p31 comet protein was proposed as a physiological negative regulator of the spindle assembly checkpoint. At the biochemical level, p31 comet binds to the closed Mad2 conformation, as it mimics the structure of the open Mad2 conformation, and thus acts as a competitive inhibitor of open-closed Mad2-binding (Mapelli et al 2006;Xia et al 2004). However, p31 comet depletion led to a weak defect in checkpoint inactivation, raising the question of the importance of this mechanism for spindle checkpoint silencing (Habu et al 2002;Xia et al 2004).…”

Section: How Is the Spindle Assembly Checkpoint Turned Off?mentioning

confidence: 99%

The Spindle Assembly Checkpoint: Clock or Domino?

Medina-Redondo

Meraldi

2011

Results and Problems in Cell Differentiation

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In each cell division, the newly duplicated chromosomes must be evenly distributed between the sister cells. Errors in this process during meiosis or mitosis are equally fatal: improper segregation of the chromosome 21 during human meiosis leads to Down syndrome (Conley, Aneuploidy: etiology and mechanisms, pp 1985), whereas in somatic cells, aneuploidy has been linked to carcinogenesis, by unbalancing the ratio of oncogenes and tumor suppressors (Holland and Cleveland, Nat Rev Mol Cell Biol 10(7): 478-487, 2009; Yuen et al., Curr Opin Cell Biol 17(6):576-582, 2005). Eukaryotic cells have developed a mechanism, known as the spindle assembly checkpoint, to detect erroneous attachment of chromosomes to the mitotic/meiotic spindle and delay the cell cycle to give enough time to resolve these defects. Research in the last 20 years, has demonstrated that the spindle assembly checkpoint is not only a pure checkpoint pathway, but plays a constitutive role in every cell cycle. Here, we review our current knowledge of how the spindle assembly checkpoint is integrated into the cell cycle machinery, and discuss some of the questions that have to be addressed in the future.

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Determinants of conformational dimerization of Mad2 and its inhibition by p31comet

Cited by 125 publications

References 47 publications

p31comet Induces Cellular Senescence through p21 Accumulation and Mad2 Disruption

p31comet Induces Cellular Senescence through p21 Accumulation and Mad2 Disruption

Modeling dual pathways for the metazoan spindle assembly checkpoint

The Spindle Assembly Checkpoint: Clock or Domino?

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