Our study implicates NEK2 in AS regulation of several SRSF1 target genes involved in cell viability

ed by Bub1 overexpression.41 On the other hand, we found increased phosphorylation of Aurora B substrates, such as Knl1,63 and an increase in the amount of Bub1 in a complex with Aurora B in Bub1 transgenic cells compared with wild type.41 More exciting was the finding that Bub1-induced chromosome segregation defects could be suppressed by partial inhibition of Aurora B.41 Additionally, cooverexpression of the Aurora B in vivo inhibitor, BubR1,64 also suppressed Bub1induced chromosome missegregation.41 In both instances, aneuploidy was also restored to near wild-type levels with Aurora B inhibition. We conclude that Bub1 overexpression drives Aurora B hyperactivation. What is the Relationship between Bub1 and Aurora B Contradictory reports in the literature have resulted in some confusion over what the molecular relationship is between Aurora B and Bub1. Namely, some reports suggest that Bub1 is upstream of Aurora B, while others have concluded that Bub1 is either downstream or in a parallel pathway as Aurora B. Evidence suggesting that Bub1 is upstream of Aurora B is based on the observation that Bub1 depletion inhibits Aurora B inner centromeric localization and results in the re-distribution of Aurora B to chromosome arms.65,66 In addition, using fission yeast and human cells, it has been observed that phosphorylation of histone H2A at threonine 120 by Bub1 kinase contributes to the recruitment of Aurora B to centromeres in a shugoshin- and Cdk1-dependent manner.54,67 These reports indicate that Bub1 is involved in Aurora B localization and thus, its error correction activity. In direct contrast, others have found that siRNA-mediated depletion of Bub1 does not delocalize centromeric Aurora B,50 that Aurora B catalysis is actually required for accumulation of Bub1 on tension-less kinetochores,68 or that Bub1 and Aurora B exist in parallel pathways for Aglafoline checkpoint signaling.69 One possible explanation for these divergent results is the difficulty in obtaining efficient and complete depletion of Bub1 by siRNA. While it is clear that Bub1 is required for mitotic progression and a robust checkpoint response,9,40,59 several experiments with Bub1 siRNA have had difficulty replicating this result.49,69 Finally, a direct link between Aurora B function and Bub1 has been suggested as it was demonstrated that Xenopus Bub1 can phosphorylate INCENP, an Aurora B modulating protein, in vitro,70 although the residue involved are not specified. Phosphorylation of INCENP, particularly at the TSS PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19821366 residues, has been implicated in Aurora B activation,71-73 whereas phosphorylation of INCENP at Thr59 and Thr388 by Cdk1 is necessary for the metaphase to anaphase transition and the recruitment of Plk1 to kinetochores.74 Interestingly, Bub1 depletion has been reported to reduce INCENP centromere/ kinetochore targeting.75 Potential Mechanisms for Bub1-Dependent Aurora B Activation The observation of increased Aurora B activity in Bub1 overexpressing cells begs the question of how Bub1 influences Aurora B activity. It is thought that Aurora B contributes to the error correction pathway through its localization at inner centromeres and activity against substrates that influence spindle microtubulekinetochore affinity.14,17,63,76 Aurora B is the enzymatic component of the chromosome passenger complex, which includes INCENP, Borealin and Survivin.76 These three proteins form a helix bundle that associates with Aurora B through the IN-box on INCENP.71,77-79 Studies o