Before and after the spindle assembly checkpoint: An APC/C Point of View

The Laboratory of Molecular and Cellular Biology, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institutes of Health, Bethesda, Maryland 20892-0840, USA.
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 10/2006; 5(18):2168-71.
Source: PubMed


On May 17-21, 2006 the Cold Spring Harbor Laboratory meeting on the cell cycle reunited over 350 researchers to discuss new findings in the cell cycle field. A common thread that connected numerous presentations was the regulation of the anaphase promoting complex/cyclosome (APC/C). This was also the main theme of the lecture given by the keynote speaker, Marc Kirschner (Harvard), who talked about "The unexpected importance of UbcH10 in both the G(1)/S transition and the initiation of anaphase", and it is also the main focus in this summary.

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    • "In late mitosis, Cdc20 is degraded by Cdh1/APC and leads to the complete replacement of Cdc20/APC by Cdh1/APC [7,8]. Recent studies demonstrated that UbcH10 supplementation promotes dissociation of the spindle assembly checkpoint proteins Mad2 and BubR1 from Cdc20, and then activates Cdc20/APC, which leads to cyclin A and securin degradation [9,10]. These results suggest that UbcH10 is potentially involved in the termination of the spindle assembly checkpoint and further implies that aberrant UbcH10 expression impairs the spindle assembly checkpoint resulting in chromosomal instability [11,12]. "
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    ABSTRACT: UbcH10 participates in proper metaphase to anaphase transition, and abrogation of UbcH10 results in the premature separation of sister chromatids. To assess the potential role of UbcH10 in colon cancer progression, we analyzed the clinicopathological relevance of UbcH10 in colon cancer. We firstly screened the expression profile of UbcH10 in various types of cancer tissues as well as cell lines. Thereafter, using the colon cancer cells line, we manipulated the expression of UbcH10 and evaluated the cell cycle profile and cellular proliferations. Furthermore, the clinicopathological significance of UbcH10 was immunohistologically evaluated in patients with colon cancer. Statistical analysis was performed using the student's t-test and Chi-square test. Using the colon cancer cells, depletion of UbcH10 resulted in suppression of cellular growth whereas overexpression of UbcH10 promoted the cellular growth and oncogenic cellular growth. Mitotic population was markedly alternated by the manipulation of UbcH10 expression. Immunohistochemical analysis indicated that UbcH10 was significantly higher in colon cancer tissue compared with normal colon epithelia. Furthermore, the clinicopathological evaluation revealed that UbcH10 was associated with high-grade histological tumors. The results show the clinicopathological significance of UbcH10 in the progression of colon cancer. Thus UbcH10 may act as a novel biomarker in patients with colon cancer.
    Full-text · Article · Feb 2009 · BMC Cancer
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    ABSTRACT: In eukaryotes, the spindle-assembly checkpoint (SAC) is a ubiquitous safety device that ensures the fidelity of chromosome segregation in mitosis. The SAC prevents chromosome mis-segregation and aneuploidy, and its dysfunction is implicated in tumorigenesis. Recent molecular analyses have begun to shed light on the complex interaction of the checkpoint proteins with kinetochores--structures that mediate the binding of spindle microtubules to chromosomes in mitosis. These studies are finally starting to reveal the mechanisms of checkpoint activation and silencing during mitotic progression.
    No preview · Article · May 2007 · Nature Reviews Molecular Cell Biology
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    ABSTRACT: The recently identified centrosome protein Nlp (ninein-like protein) is a key regulator in centrosome maturation, which contributes to chromosome segregation and cytokinesis. However, the mechanism(s) controlling Nlp expression remains largely unknown. Here we have shown that Nlp expression is cell cycle-dependent with a peak at G(2)/M transition in human cells. Nlp is a short-lived protein and degraded by the proteasome via the anaphase-promoting cyclosome complex (APC/c) pathway. It interacts with the APC/c through the APC2 or Cdc27 subunits and is ubiquitinated. Following treatment with proteasome inhibitors, its protein level is elevated. Nlp binds in vivo to the degradation-targeting proteins Cdh1 and Cdc20, and overexpression of Cdh1 and Cdc20 enhances Nlp degradation. Using point mutations of the two putative degradation signals in Nlp, we have found that its degradation requires intact KEN-box and D-box. Interestingly, the Lys-Glu-Asn-D-box-mutated Nlp exhibits a much stronger capability of inducing anchorage-independent growth and multinuclearity compared with the wild type Nlp. Taken together, these findings indicate that Nlp expression is cell cycle-dependent and regulated by APC-mediated protein degradation.
    No preview · Article · Jun 2007 · Journal of Biological Chemistry
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