Abstract
Activation of the mitotic checkpoint requires the precise timing and spatial organization of mitotic regulatory events, and ensures accurate chromosome segregation. Mitotic checkpoint proteins such as BubR1 and Mad2 bind to Cdc20, and inhibit anaphase-promoting complex/cyclosome(Cdc20)-mediated securin degradation and the onset of anaphase. BubR1 mediates the proper attachment of microtubules to kinetochores, and links the regulation of chromosome-spindle attachment to mitotic checkpoint signaling. Therefore, disruption of BubR1 activity results in a loss of the checkpoint control, chromosome instability, and/or early onset of malignancy. In this study, we show that BubR1 directly interacts with securin in vitro and in vivo. In addition, the BubR1 interaction contributes to the stability of securin, and there is a significant positive correlation between BubR1 and securin expressions in human cancer. Importantly, BubR1 competes with Cdc20 for binding to securin, and thereby the interaction between BubR1 and securin is greatly increased by the depletion of Cdc20. Our findings may identify a novel regulation of BubR1 that can generate an additional anaphase-inhibitory signal through the Cdc20-independent interaction of BubR1 with securin.
Highlights
The mitotic spindle checkpoint ensures accurate segregation of mitotic chromosomes by delaying anaphase onset until each kinetochore has correctly attached to the mitotic spindle
Cells that overexpress Cdc20 greatly reduced the mitotic arrest in response to spindle damage, www.aacrjournals.org presumably because increased levels of Cdc20 activate anaphase-promoting complex/cyclosome (APC/C) and allow cells to bypass the mitotic checkpoint [10, 32, 33]
Coexpression of BubR1 restored the mitotic arrest of the Cdc20overexpressing cells [10], indicating that BubR1 directly inhibits the activity of APC/CCdc20
Summary
The mitotic spindle checkpoint ensures accurate segregation of mitotic chromosomes by delaying anaphase onset until each kinetochore has correctly attached to the mitotic spindle. Various mitotic checkpoint proteins including Bub, BubR1, Bub, and Mad are recruited to kinetochores that lack attachments or tension to generate a ‘‘wait anaphase’’ signal through the formation of an inhibitory ternary complex known as the mitotic checkpoint complex The mitotic spindle checkpoint ensures that activation of the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase, is delayed until all chromosomes have achieved bipolar kinetochoremicrotubule attachment [7,8,9]. MCC formation is facilitated by the binding of BubR1 and Mad to Cdc, which is a crucial cofactor of the APC/C and is the main target of the mitotic spindle checkpoint. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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