RESEARCH HIGHLIGHTS Nature Reviews Molecular Cell Biology | AOP, published online 14 May 2014; doi:10.1038/nrm3809
C E L L C YC L E
Regulating chromosome segregation Cyclin B1 and cyclin B2 have been implicated in cell cycle regulation through the activation of key regulators of early mitotic events, such as cyclin-dependent kinase 1 (CDK1). CDK1–cyclin B1 coordinates anaphase onset by phosphorylating separase to prevent cleavage of the cohesin complex, which holds sister chromatids together until kinetochores are properly attached to spindle microtubules. By contrast, the role of cyclin B2 is less well established. Increased cyclin B1 and cyclin B2 levels are associated with tumour aggressiveness and poor clinical outcome; however, the role of these proteins in tumorigenesis remained elusive. Nam and van Deursen now report that over expression of cyclin B1 or cyclin B2 in mice causes distinct chromosome segregation defects, and they identify a role for cyclin B2 in centrosome separation. The authors found that aneuploidy rates and tumour susceptibility were increased in transgenic mice overexpressing cyclin B1 and cyclin B2. Moreover, live cell imaging revealed that chromosome segregation was
cyclin B2 and p53 function antagon istically to coordinate centrosome separation
NPG
defective in mouse embryonic fibroblasts (MEFs) that were derived from these mice. Interestingly, overexpression of cyclin B1 led to the formation of chromosome bridges and anaphase failure, whereas increased cyclin B2 levels caused lagging chromosomes, which suggests that these cyclins perturb chromosome segregation through distinct mechanisms. The authors went on to show that high cyclin B1 levels correlated with CDK1 hyperactivity, which caused the continued inhibition of separase activity, and, as a result, homologous chromosomes were unable to properly segregate. Overexpression of cyclin B2, but not of cyclin B1, led to abnormal spindle geometry and accelerated centrosome separation. Furthermore, the authors showed that the activity of Aurora A kinase and its substrate, Polo-like kinase 1 (PLK1; a key regulator of centrosome separation), was increased in these cells. Inhibition of PLK1 reduced spindle geometry defects, precocious centrosome splitting and aneuploidy, which indicates that increased cyclin B2 levels lead to chromosome missegregation through Aurora A-mediated PLK1 activation.
NATURE REVIEWS | MOLECULAR CELL BIOLOGY
Importantly, depletion of cyclin B2 in wildtype MEFs reduced the centrosomal location of Aurora A and PLK1 and inhibited centrosome disjunction, which suggests that endogenous cyclin B2 has a role in this process. The authors also noticed that centrosome separation was not impaired in cyclin B2‑depleted immortalized MEFs that lack the tumour suppressor p53, which is known to negatively regulate Aurora A transcription. Knocking out the gene encoding p53 in MEFs resulted in increased Aurora A protein abundance and phosphorylation, rapid centrosome separation, asymmetrical spindles and chromosome lagging. These findings suggest that p53 controls centrosome separation by negatively regulating Aurora A. In summary, this study shows that cyclin B1 and cyclin B2 regulate chromosome segregation through distinct mechanisms and uncovers a novel mechanism whereby cyclin B2 and p53 function antagonistically to coordinate centrosome separation.
Andrea Du Toit
ORIGINAL RESEARCH PAPER Nam, H.-J. & van Deursen, J. M. Cyclin B2 and p53 control proper timing of centrosome separation. Nature Cell Biol. http://dx.doi.org/10.1038/ncb2952 (2014)
VOLUME 15 | JUNE 2014 © 2014 Macmillan Publishers Limited. All rights reserved
C E L L C YC L E
Regulating chromosome segregation Cyclin B1 and cyclin B2 have been implicated in cell cycle regulation through the activation of key regulators of early mitotic events, such as cyclin-dependent kinase 1 (CDK1). CDK1–cyclin B1 coordinates anaphase onset by phosphorylating separase to prevent cleavage of the cohesin complex, which holds sister chromatids together until kinetochores are properly attached to spindle microtubules. By contrast, the role of cyclin B2 is less well established. Increased cyclin B1 and cyclin B2 levels are associated with tumour aggressiveness and poor clinical outcome; however, the role of these proteins in tumorigenesis remained elusive. Nam and van Deursen now report that over expression of cyclin B1 or cyclin B2 in mice causes distinct chromosome segregation defects, and they identify a role for cyclin B2 in centrosome separation. The authors found that aneuploidy rates and tumour susceptibility were increased in transgenic mice overexpressing cyclin B1 and cyclin B2. Moreover, live cell imaging revealed that chromosome segregation was
cyclin B2 and p53 function antagon istically to coordinate centrosome separation
NPG
defective in mouse embryonic fibroblasts (MEFs) that were derived from these mice. Interestingly, overexpression of cyclin B1 led to the formation of chromosome bridges and anaphase failure, whereas increased cyclin B2 levels caused lagging chromosomes, which suggests that these cyclins perturb chromosome segregation through distinct mechanisms. The authors went on to show that high cyclin B1 levels correlated with CDK1 hyperactivity, which caused the continued inhibition of separase activity, and, as a result, homologous chromosomes were unable to properly segregate. Overexpression of cyclin B2, but not of cyclin B1, led to abnormal spindle geometry and accelerated centrosome separation. Furthermore, the authors showed that the activity of Aurora A kinase and its substrate, Polo-like kinase 1 (PLK1; a key regulator of centrosome separation), was increased in these cells. Inhibition of PLK1 reduced spindle geometry defects, precocious centrosome splitting and aneuploidy, which indicates that increased cyclin B2 levels lead to chromosome missegregation through Aurora A-mediated PLK1 activation.
NATURE REVIEWS | MOLECULAR CELL BIOLOGY
Importantly, depletion of cyclin B2 in wildtype MEFs reduced the centrosomal location of Aurora A and PLK1 and inhibited centrosome disjunction, which suggests that endogenous cyclin B2 has a role in this process. The authors also noticed that centrosome separation was not impaired in cyclin B2‑depleted immortalized MEFs that lack the tumour suppressor p53, which is known to negatively regulate Aurora A transcription. Knocking out the gene encoding p53 in MEFs resulted in increased Aurora A protein abundance and phosphorylation, rapid centrosome separation, asymmetrical spindles and chromosome lagging. These findings suggest that p53 controls centrosome separation by negatively regulating Aurora A. In summary, this study shows that cyclin B1 and cyclin B2 regulate chromosome segregation through distinct mechanisms and uncovers a novel mechanism whereby cyclin B2 and p53 function antagonistically to coordinate centrosome separation.
Andrea Du Toit
ORIGINAL RESEARCH PAPER Nam, H.-J. & van Deursen, J. M. Cyclin B2 and p53 control proper timing of centrosome separation. Nature Cell Biol. http://dx.doi.org/10.1038/ncb2952 (2014)
VOLUME 15 | JUNE 2014 © 2014 Macmillan Publishers Limited. All rights reserved
