Identification of a MAD2-binding protein, CMT2, and its role in mitosis

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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“…On microtubule attachment, the p31 comet protein specifically interacts with closed Mad2 but not open Mad2 (7,8).…”

Section: Discussionmentioning

confidence: 99%

“…p31 comet was initially identified as a Mad2-interacting protein (7). 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.…”

Section: Introductionmentioning

confidence: 99%

p31comet Induces Cellular Senescence through p21 Accumulation and Mad2 Disruption

Yun

Han

Yoon

et al. 2009

Molecular Cancer Research

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“…One possible mechanism is the disruption of APC/C inhibitory complexes. A candidate protein that may participate in this process is Cmt2p, which binds to Mad2p in vivo at the same time that Mad2p dissociates from the APC/C [Habu et al, 2002]. Because overproduction of Cmt2p prevents SAC activation, Cmt2p-Mad2p binding may directly inhibit SAC signaling [Habu et al, 2002].…”

Section: Silencing the Spindle Checkpointmentioning

confidence: 99%

“…A candidate protein that may participate in this process is Cmt2p, which binds to Mad2p in vivo at the same time that Mad2p dissociates from the APC/C [Habu et al, 2002]. Because overproduction of Cmt2p prevents SAC activation, Cmt2p-Mad2p binding may directly inhibit SAC signaling [Habu et al, 2002]. Another mechanism of disrupting APC/C inhibitory complexes may involve phosphorylation of Mad2p [Wassmann et al, 2003].…”

Section: Silencing the Spindle Checkpointmentioning

confidence: 99%

SAC‐ing mitotic errors: How the spindle assembly checkpoint (SAC) plays defense against chromosome mis‐segregation

Kadura

Sazer

2005

Cell Motil. Cytoskeleton

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“…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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Identification of a MAD2-binding protein, CMT2, and its role in mitosis

Cited by 143 publications

References 59 publications

p31comet Induces Cellular Senescence through p21 Accumulation and Mad2 Disruption

p31comet Induces Cellular Senescence through p21 Accumulation and Mad2 Disruption

SAC‐ing mitotic errors: How the spindle assembly checkpoint (SAC) plays defense against chromosome mis‐segregation

The Spindle Assembly Checkpoint: Clock or Domino?

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