title: p31comet Induces cellular senescence through p21 accumulation and Mad2 disruption.
abstract: 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.
authors.affiliation: Laboratory of Radiation Molecular Cancer, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Miyong
authors.initials: M
authors.lastname: Yun
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Han
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Yoon
authors.forename: Hee Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Bu-Yeo
authors.initials: BY
authors.lastname: Kim
authors.forename: Yeun-Jin
authors.initials: YJ
authors.lastname: Ju
authors.forename: Chang-Mo
authors.initials: CM
authors.lastname: Kang
authors.forename: Su Hwa
authors.initials: SH
authors.lastname: Jang
authors.forename: Hee-Yong
authors.initials: HY
authors.lastname: Chung
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Myung-Haing
authors.initials: MH
authors.lastname: Cho
authors.forename: Gyesoon
authors.initials: G
authors.lastname: Yoon
authors.forename: Gil Hong
authors.initials: GH
authors.lastname: Park
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Kee-Ho
authors.initials: KH
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000502:physiology*; D002999:Clone Cells; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D006801:Humans; D064246:Mad2 Proteins; D008938:Mitosis / Q000502:physiology; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D001616:beta-Galactosidase / Q000096:biosynthesis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C493956:CDKN1A protein, human; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C577697:MAD2L1 protein, human; C470309:MAD2L1BP protein, human; D064246:Mad2 Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004247:DNA; D001616:beta-Galactosidase