title: Cdk1-phosphorylated CUEDC2 promotes spindle checkpoint inactivation and chromosomal instability.
abstract: Aneuploidy and chromosomal instability are major characteristics of human cancer. These abnormalities can result from defects in the spindle assembly checkpoint (SAC), which is a surveillance mechanism for accurate chromosome segregation through restraint of the activity of the anaphase-promoting complex/cyclosome (APC/C). Here, we show that a CUE-domain-containing protein, CUEDC2, is a cell-cycle regulator that promotes spindle checkpoint inactivation and releases APC/C from checkpoint inhibition. CUEDC2 is phosphorylated by Cdk1 during mitosis. Depletion of CUEDC2 causes a checkpoint-dependent delay of the metaphase-anaphase transition. Phosphorylated CUEDC2 binds to Cdc20, an activator of APC/C, and promotes the release of Mad2 from APC/C-Cdc20 and subsequent APC/C activation. CUEDC2 overexpression causes earlier activation of APC/C, leading to chromosome missegregation and aneuploidy. Interestingly, CUEDC2 is highly expressed in many types of tumours. These results suggest that CUEDC2 is a key regulator of mitosis progression, and that CUEDC2 dysregulation might contribute to tumour development by causing chromosomal instability.
authors: Institute of Basic Medical Sciences, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China.
authors: Yan-Fei
authors: YF
authors: Gao
authors: Teng
authors: T
authors: Li
authors: Yan
authors: Y
authors: Chang
authors: Yu-Bo
authors: YB
authors: Wang
authors: Wei-Na
authors: WN
authors: Zhang
authors: Wei-Hua
authors: WH
authors: Li
authors: Kun
authors: K
authors: He
authors: Rui
authors: R
authors: Mu
authors: Cheng
authors: C
authors: Zhen
authors: Jiang-Hong
authors: JH
authors: Man
authors: Xin
authors: X
authors: Pan
authors: Tao
authors: T
authors: Li
authors: Liang
authors: L
authors: Chen
authors: Ming
authors: M
authors: Yu
authors: Bing
authors: B
authors: Liang
authors: Yuan
authors: Y
authors: Chen
authors: Qing
authors: Q
authors: Xia
authors: Tao
authors: T
authors: Zhou
authors: Wei-Li
authors: WL
authors: Gong
authors: Ai-Ling
authors: AL
authors: Li
authors: Hui-Yan
authors: HY
authors: Li
authors: Xue-Min
authors: XM
authors: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D064173:Anaphase-Promoting Complex-Cyclosome; D000782:Aneuploidy; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D043171:Chromosomal Instability / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D064246:Mad2 Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D008938:Mitosis / Q000235:genetics / Q000502:physiology; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D012097:Repressor Proteins / Q000378:metabolism; D008941:Spindle Apparatus / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C519556:CUEDC2 protein, human; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D012097:Repressor Proteins; C577488:CDC20 protein, human; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D016203:CDC2 Protein Kinase