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Aurora B and INCENP co-overexpression severely disrupts mitosis and distinctly modifies the global transcriptional landscape [ChIP-seq]

ABSTRACT: Aurora B kinase, as part of the chromosomal passenger complex (CPC), controls key processes during the cell cycle such as DNA compaction, genome partitioning or cytokinesis. Nonetheless, increased Aurora B levels are a potential threat for the cells and have been linked to different tumor types. We have carried out an exhaustive characterization of the global consequences of the overexpression of Aurora B and INCENP, the scaffold of the CPC and an activator of Aurora B kinase activity, in non-transformed human cells. Our data demonstrate, not only that an individual increase in the levels of Aurora B or INCENP have a different impact on the cells, but more importantly that their simultaneous overexpression stabilizes both CPC components, exacerbates Aurora B activity, severely impairs mitotic progression and chromosome dynamics, and has a distinctive and more dramatic effect on the transcriptional landscape of the cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273668 | GEO | 2025/05/06

REPOSITORIES: GEO

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Aurora B and INCENP co-overexpression severely disrupts mitosis and distinctly modifies the global transcriptional landscape [RNA-seq]

Project description:Aurora B kinase, as part of the chromosomal passenger complex (CPC), controls key processes during the cell cycle such as DNA compaction, genome partitioning or cytokinesis. Nonetheless, increased Aurora B levels are a potential threat for the cells and have been linked to different tumor types. We have carried out an exhaustive characterization of the global consequences of the overexpression of Aurora B and INCENP, the scaffold of the CPC and an activator of Aurora B kinase activity, in non-transformed human cells. Our data demonstrate, not only that an individual increase in the levels of Aurora B or INCENP have a different impact on the cells, but more importantly that their simultaneous overexpression stabilizes both CPC components, exacerbates Aurora B activity, severely impairs mitotic progression and chromosome dynamics, and has a distinctive and more dramatic effect on the transcriptional landscape of the cells.

2025-05-06 | GSE273663 | GEO

Transcriptome analysis of NCC-IT-A3 cells by Barasertib treatment

Project description:During mitosis, the chromosomal passenger complex (CPC) that is formed by Aurora-B, INCENP, Survivin, and Borealin ensures the faithful segregation of the chromosomes into daughter cells. We previously have shown that CPC activity was terminated by the anaphase promoting complex/cyclosome (APC/C) and its cofactor Cdh1 via ubiquitylation of Borealin and Aurora-B during the G1 phase of somatic cells. On the other hand, protein levels of Borealin and Aurora-B were stable during cell cycle progression due to high levels of Emi1, which keep APC/CCdh1 inactive in embryonal carcinoma (EC) cells. During retinoic acid-induced differentiation of EC cells, these proteins were downregulated by APC/CCdh1-mediated ubiquitylation. Interestingly, CPC proteins form a complex with Aurora-B kinase activity even in interphase of EC cells. Significantly, inhibition of CPC activity by either knockdown of Borealin or Aurora-B and Aurora-B kinase inhibitor treatment induced spontaneous differentiation of EC cells. In conclusion, sustained CPC activity plays a critical role in maintenance of the undifferentiated state of pluripotent stem cells. We therefore propose an interphase role of the CPC in regulating embryonic pluripotency.

2021-07-09 | GSE179503 | GEO

Aurora B and INCENP co-overexpression severely disrupts mitosis and distinctly modifies the global transcriptional landscape

Project description:Aurora B and INCENP co-overexpression severely disrupts mitosis and distinctly modifies the global transcriptional landscape

| PRJNA1142593 | ENA

Aurora B and INCENP co-overexpression severely disrupts mitosis and distinctly modifies the global transcriptional landscape [ChIP-seq]

Project description:Aurora B and INCENP co-overexpression severely disrupts mitosis and distinctly modifies the global transcriptional landscape [ChIP-seq]

| PRJNA1142597 | ENA

Aurora B and INCENP co-overexpression severely disrupts mitosis and distinctly modifies the global transcriptional landscape [RNA-seq]

Project description:Aurora B and INCENP co-overexpression severely disrupts mitosis and distinctly modifies the global transcriptional landscape [RNA-seq]

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Aurora A kinase phosphorylates Hec1 to regulate metaphase kinetochore-microtubule dynamics.

Project description:Precise regulation of kinetochore-microtubules is essential for successful chromosome segregation. Central to this regulation is Aurora B kinase, which phosphorylates kinetochore substrates to promote microtubule turnover. A critical target of Aurora B is the N-terminal “tail” domain of Hec1/NDC80, which is a component of the NDC80 complex, a force-transducing link between kinetochores and microtubules. While Aurora B is regarded as the “master regulator” of kinetochore-microtubule attachment, it is likely that other mitotic kinases contribute to Hec1phosphorylation. Here we show that Aurora A kinase phosphorylates the tail domain of Hec1 at Serine 69, a previously uncharacterized phosphorylation target site, and plays an important role in controlling kinetochore-microtubule attachment dynamics. Using phospho-specific antibodies, Hec1 phospho-deficient mutants, and kinase inhibitors, we demonstrate that Aurora A is required for the regulation of kinetochore-microtubule dynamics of metaphase chromosomes and identify Hec1 Serine 69 as a critical Aurora A substrate for this regulation. Additionally, we demonstrate that Aurora A kinase associates with INCENP during mitosis and that INCENP is competent to drive accumulation of the kinase to the centromere region of mitotic chromosomes. These findings reveal that both Aurora A and Aurora B contribute to kinetochore-microtubule attachment dynamics, and they uncover an unexpected role for Aurora A in mitosis.

2017-11-28 | PXD006892 | Pride

Gene expression changes in medulloblastoma due to Myc overexpression and Mitotic inhibition with AZD1152 Aurora Kinase B Inhibitior

Project description:Sonic hedgehog medulloblastoma cells with stable overexpression of Myc (UW426-Myc) become sensitized to apoptosis induction when exposed to Aurora kinase B inhibitor AZD1152. We sought to determine the gene expression changes that take place when Myc is overexpressed in UW426 and to determine the genes differentially expressed in UW426-Myc cells compared to wild-type UW426 when exposed tothe drug AZD1152 that specifically inhibits Aurora kinase B activity.

2021-04-01 | GSE159385 | GEO

Simultaneous silencing of Aurora-A and UHRF1 inhibits colorectal cancer cell growth by regulating the expression of DNMT1 and STAT1

Project description:Aurora-A has attracted a great deal of interest as a potential therapeutic target. However, the outcomes of inhibitors targeting Aurora-A are not as favorable as expected, and the basis of their ineffectiveness remains unknown. Here, we found that signal transducer and activator of transcription 1 (STAT1) was highly expressed in colorectal cancer (CRC) xenograft mouse models that were resistant to alisertib, an Aurora-A inhibitor, in an interferon/Janus kinase-independent manner, suggesting an unconventional mechanism regulating STAT1 expression. Unexpectedly, we found that alisertib disrupted Aurora-A binding with ubiquitin-like with plant homeodomain and ring finger domain 1 (UHRF1), leading to UHRF1-mediated ubiquitination and degradation of DNA methyltransferase 1 (DNMT1), which in turn resulted in demethylation of the CpG islands in the STAT1 promoter and STAT1 overexpression. Simultaneous silencing of Aurora-A and UHRF1 prevented STAT1 overexpression and effectively inhibited CRC growth. Hence, concomitant targeting of Aurora-A and UHRF1 can be a promising therapeutic strategy for cancer patients.

2020-10-26 | GSE160037 | GEO

Aurora-A phosphorylates splicing factors and regulates alternative splicing

Project description:The goal of this study is to identify the effect of inhibition of Aurora-A kinase activity on gene expression and RNA splicing. The perturbation of Aurora-A is well known to affect cell cycle distribution. Therefore, we coupled the inhibition of Aurora-A with cell synchronization procedure in order to avoid the indirect effect of cell cycle perturbation on splicing changes. The mRNA -seq libraries were prepared and subjected to paired-end sequencing on Illumina HiSeq 2500 lanes. Differential gene expression and splicing analysis were carried using the edgeR tool and VAST-tools respectively. The RNA seq analysis identified that pharmacological inhibition of Aurora-A affects alternative splicing of 505 genes while having a marginal effect on gene expression. Overall our work identified Aurora-A as a novel splicing kinase and for the first time, describes a broad role of Aurora-A in regulating alternative splicing.

2024-11-21 | GSE160733 | GEO

MKLP2 walks along microtubules and takes the CPC along for a ride

Project description:The mitotic kinesin-like Protein 2 (MKLP2, KIF20A) is essential for the proper execution of cytokinesis and required to ‘passage’ the chromosomal passenger complex (CPC) from the chromosomes in (pro)metaphase to the spindle midzone and equatorial cortex in anaphase. Together with MKLP1 (KIF23) and MPP1 (KIF20B), MKLP2 forms the kinesin-6 subfamily of motor proteins. Whilst MKLP1 and MPP1 are both plus-end directed processive motors, the typical structure of the MKLP2 motor domain along with the extended neck-linker region, suggested that MKLP2 might not be able to function as a transport motor but is more likely to act as a microtubule bundler. This notion contradicts the prevailing hypothesis that MKLP2 can transport the CPC in anaphase, but appears to be in line with in vitro and in cellulo studies showing that recombinant MKLP2 efficiently bundles microtubules, and that knock-down of MKLP2, disturbs the organization of the anaphase spindle midzone. Using TIRF microscopy and purified fluorescent proteins, we here demonstrate that MKLP2 is a plus-end directed processive motor that can transport the CPC along microtubules in vitro. Live imaging of MKLP2::GFP and INCENP::GFP in early anaphase cells revealed that a fraction of both MKLP2 and INCENP displays directed movements towards the (equatorial) cortex. In line, inhibition of MKLP2 ATPase activity at the start of anaphase disturbed the localization of MKLP2 and CPC at the equatorial cortex. Our data suggest that MKLP2 is a processive microtubule-based motor that transports itself and the CPC to the equatorial cortex.

2020-06-10 | PXD014665 | Pride

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