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Cdk1-phosphorylated CUEDC2 promotes spindle checkpoint inactivation and chromosomal instability.

Nature cell biology | Aug 2, 2011

http://www.ncbi.nlm.nih.gov/pubmed/21743465

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.

Pubmed ID: 21743465 RIS Download

Mesh terms: Anaphase-Promoting Complex-Cyclosome | Aneuploidy | CDC2 Protein Kinase | Calcium-Binding Proteins | Carrier Proteins | Cdc20 Proteins | Cell Cycle Proteins | Cell Transformation, Neoplastic | Chromosomal Instability | HeLa Cells | Humans | Mad2 Proteins | Membrane Proteins | Mitosis | Multiprotein Complexes | Neoplasms | Phosphorylation | Repressor Proteins | Spindle Apparatus | Ubiquitin-Protein Ligase Complexes

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