Overexpression of Aurora-C interferes with the spindle checkpoint by promoting the degradation of Aurora-B

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.

H3 Thr3 phosphorylation is crucial for meiotic resumption and anaphase onset in oocyte meiosis

“…Given the fact that loss of Aurora kinase activity can also induce premature anaphase onset, 32,35 and that H3T3-P is a prerequisite for Aurora C localization to the ICA in mouse oocytes, 14 we attribute the defects of SAC to loss of Aurora C function, which is consistent with the idea that H3T3-P-dependent Aurora CPC function plays a role in SAC activation through phosphorylating and targeting SAC proteins to the kinetochore region. 15,29,32,36 Consistent with recent published data, 14 we observed a delay in anaphase onset in oocytes, even after 17 h incubation, when 5-ITu was administered from the early meiotic stages, either GV or GVBD, that may be due to the fact that chromatin was not fully condened into typical chromosome structure. We tend to believe that different drug application time produces different effects, suggesting H3T3-P regulates meiotic progression at multi steps.…”

Haspin inhibition reveals functional differences of interchromatid axis–localized AURKB and AURKC

“…AURKB localizes with microtubules of meiotic spindles ( Balboula and Schindler, 2014 ) and likely comes into close proximity to kinetochores and can regulate recruitment of SAC components like MAD2 ( Figure 5 ). When both AURKs are present, AURKC may suppress or displace AURKB activation of the SAC, as previously seen in mitotic cells with overexpression of AURKC, resulting in reduced CPC expression and weakened AURKB activity ( Lin et al , 2014 ). Only in the absence of AURKC can AURKB activate the SAC ( Figure 5 ).…”

Differential regulation of H3S10 phosphorylation, mitosis progression and cell fate by Aurora Kinase B and C in mouse preimplantation embryos

“…Despite their similarities in the protein structure and cellular localization at chromosome passenger complex, AurkC displayed unique characteristics different from AurkB. Lin et al showed that in cancer cells, overexpression of AurkC could displace AurkB from centromere and impaired SAC function (Lin et al, 2014 ). Our previous results also showed that high level AurkC in mouse oocytes accelerated securin degradation, caused chromosome mis-alignment and cytokinesis failure (Sharif et al, 2010 ).…”

“…AurkC is a mammalian specific Aurora kinase closely related to AurkB (Carmena and Earnshaw, 2003 ; Lin et al, 2014 ; Sasai et al, 2004 ). It is specially highly expressed in mammalian gamete and required for spermatocyte meiosis (Dieterich et al, 2007 ).…”