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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Anaphase-Promoting Complex-Cyclosome
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Aneuploidy
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CDC2 Protein Kinase / metabolism*
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Calcium-Binding Proteins / metabolism
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Carrier Proteins / metabolism*
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Cdc20 Proteins
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Cell Cycle Proteins / metabolism
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology
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Chromosomal Instability / genetics
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Chromosomal Instability / physiology*
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HeLa Cells
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Humans
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Mad2 Proteins
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Membrane Proteins / metabolism*
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Mitosis / genetics
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Mitosis / physiology
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Multiprotein Complexes
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Neoplasms / genetics
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Neoplasms / metabolism
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Neoplasms / pathology
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Phosphorylation
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Repressor Proteins / metabolism
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Spindle Apparatus / metabolism*
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Ubiquitin-Protein Ligase Complexes / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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CUEDC2 protein, human
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Calcium-Binding Proteins
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Carrier Proteins
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Cdc20 Proteins
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Cell Cycle Proteins
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MAD2L1 protein, human
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Mad2 Proteins
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Membrane Proteins
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Multiprotein Complexes
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Repressor Proteins
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CDC20 protein, human
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Ubiquitin-Protein Ligase Complexes
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Anaphase-Promoting Complex-Cyclosome
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CDC2 Protein Kinase