Abstract
The chromosomal passenger complex (CPC) plays a pivotal role in controlling accurate chromosome segregation and cytokinesis during cell division. Aurora-B, one of the chromosomal passenger proteins, is important for the mitotic spindle assembly checkpoint (SAC). Previous reports noted that Aurora-C is predominantly expressed in male germ cells and has the same subcellular localization as Aurora-B. Increasing evidence indicates that Aurora-C is overexpressed in many somatic cancers, although its function is uncertain. Our previous study showed that the aberrant expression of Aurora-C increases the tumorigenicity of cancer cells. Here, we demonstrate that overexpressed Aurora-C displaces the centromeric localization of CPCs, including INCENP, survivin, and Aurora-B. When cells were treated with nocodazole to turn on SAC, both the Aurora-B protein stability and kinase activity were affected by overexpressed Aurora-C. As a result, the activation of spindle checkpoint protein, BubR1, and phosphorylation of histone H3 and MCAK were also eliminated in Aurora-C-overexpressing cells. Thus, our results suggest that aberrantly expressed Aurora-C in somatic cancer cells may impair SAC by displacing the centromeric localization of CPCs.
Highlights
chromosomal passenger complex (CPC) has multiple functions during cell division, including correcting errors in chromosome segregation, regulating the mitotic ckeckpoint and cytokinesis, and maintaining genomic stability.[2]
In this study we found that overexpressed Aurora-C reduced the expression and displaced the centromeric localization of the CPC components independent of its kinase activity, thereby interfering with Aurora-B kinase activity
The centromeric localization of Aurora-C-GFP was independent of its kinase activity, as the overexpressed Aurora-C-GFP kinase hyperactive (KA) and kinase-dead (KD) mutants (Figure 1b, details in Materials and Methods) had the same subcellular localization as the Aurora-C-GFP wild type (WT) (Figure 1c)
Summary
CPC has multiple functions during cell division, including correcting errors in chromosome segregation, regulating the mitotic ckeckpoint and cytokinesis, and maintaining genomic stability.[2] Activation of the CPC depends on AuroraB activity. Aurora-B is the only protein within the CPC that has enzymatic activity. CPC components are required for the localization and function of the CPC and are necessary for the activation of Aurora-B.3–5. Activated Aurora-B phosphorylates its substrates for their functions during cell division. More than 50 proteins have been identified as Aurora-B substrates, including the CPC components, histone H3, and MCAK.[2] Dysregulation of Aurora-B results in cytokinesis failure and polyploidy, and leads to chromosome instability, a hallmark of tumorigenesis.[6]. Aurora-C and Aurora-B are oppositely expressed in human colorectal cancer tissues. The mechanism by which Aurora-C disrupts the localization and decreases the expression of Aurora-B remains unclear
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