Direct Phosphorylation and Stabilization of MYC by Aurora B Kinase Promote T Cell Leukemogenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA590732 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10502962_1.fastq.gz | Fastqsanger.gz | |||
| SRR10502962_2.fastq.gz | Fastqsanger.gz | |||
| SRR10502963_1.fastq.gz | Fastqsanger.gz | |||
| SRR10502963_2.fastq.gz | Fastqsanger.gz | |||
| SRR10502964_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
Project description:The significance of MYC deregulation has been well-documented in T-cell acute lymphoblastic leukemia (T-ALL). MYC acts as an oncogenic driver in T-ALL and particularly in maintaining leukemia-initiating cell activity. Protein interactome analysis identified Aurora B kinase (AURKB) as a specific MYC binding partner and depletion of AURKB reduced the steady-state levels of MYC. Mechanistic studies demonstrated that AURKB directly phosphorylated MYC and promoted MYC protein stability, and conversely AURKB deficiency elicited rapid MYC degradation. We thus predicted that abrogation of AURKB would affect global MYC transcriptional program. To assess the transcriptional change in response to AURKB knockdown, RNA-Seq was performed using AURKB or control-depleted CUTLL1 cells.
2020-02-11 | GSE140739 | GEO
Project description:Deregulation of MYC plays an essential role in T cell acute lymphoblastic leukemia (T-ALL), yet the mechanisms underlying its deregulation remain elusive. Herein, we identify a molecular mechanism responsible for reciprocal activation between Aurora B kinase (AURKB) and MYC. AURKB directly phosphorylates MYC at serine 67, counteracting GSK3?-directed threonine 58 phosphorylation and subsequent FBXW7-mediated proteasomal degradation. Stabilized MYC, in concert with T cell acute lymphoblastic leukemia 1 (TAL1), directly activates AURKB transcription, constituting a positive feedforward loop that reinforces MYC-regulated oncogenic programs. Therefore, inhibitors of AURKB induce prominent MYC degradation concomitant with robust leukemia cell death. These findings reveal an AURKB-MYC regulatory circuit that underlies T cell leukemogenesis, and provide a rationale for therapeutic targeting of oncogenic MYC via AURKB inhibition.
| S-EPMC7321798 | biostudies-literature
Project description:FOXA1 serves as a crucial pioneer transcription factor in developmental processes, and plays a pivotal role as a mitotic bookmarking factor to perpetuate gene expression profiles and maintain cellular identity. During mitosis, the majority of FOXA1 dissociates from specific DNA binding sites and redistributes to non-specific binding sites, however, the regulatory mechanisms governing FOXA1's molecular dynamics in mitosis remain elusive. Here we show that mitotic kinase Aurora B regulates FOXA1's different DNA binding modes and the formation of the biomolecular condensate. Mechanistically, Aurora B kinase phosphorylates FOXA1 at Serine 221 (S221) to disrupt the specific, but not the non-specific, DNA binding. The phosphorylation of S221 also negatively regulates the FOXA1 condensates that require specific DNA binding. Importantly, perturbation of the dynamic phosphorylation impairs accurate gene reactivations and cell proliferation, suggesting that reversible mitotic protein phosphorylation emerges as a fundamental mechanism for the spatiotemporal control of mitotic bookmarking.
2024-08-31 | GSE273759 | GEO
Project description:Genome-wide distribution of proteins and histone marks in CD43 negative mouse resting B cells ChIP-seq analyses of Aurora B, Ring1B, Bcx7, USP16, H3K27me3, and Ezh2 were carried out on wild-typeCD43 negative resting B cells. ChIP-seq datasets obtained from Aurora B knockout and RingiB knockout cells were used as negative controls to validate the signals for Aurora B and Ring1B from wild-type cells. 8WG16 ChIP-seq datasets were generated from WT (Cre-ERt2 homozygous) and Ring1B KO (Cre-ERt2/Rnf2 flox homozygous). RNAP-S5ph ChIP-seq datasets were generated from WT (Cre-ERt2 homozygous) and Aurkb KO (Cre-ERt2/Aurkb flox homozygous). ChIP-seq analyses of H3S28 phosphorylation (H3S28ph) and H2AK119 monoubiquitination (H2Aub1) in wild-type (Cre-ERt2 homozygous) and Aurora B KO (Cre-ERt2/Aurkb flox homozygous) CD43 negative resting B cells treated with 250nM tamoxifen (4-hydroxytamoxifen) for 48 hours. ChIP-seq analyses of the levels of unphosphorylated RNA Pol II (8WG16) and serine 5-phosphorylated RNA Pol II (RNAP-S5ph) were conducted in Aurkb KO (Cre-ERt2/Aurkb flox homozygous) and Ring1B KO (Cre-ERt2/Rnf2 flox homozygous) CD43 negative resting B cells treated with 250nM tamoxifen (4-hydroxytamoxifen) for 48 hours respectively). All libraries were prepared from sonicated, formaldehyde-crossilinked chromatin. For H2Aub1, ChIP was performed using micrococcal nuclease-digested, unfixed chromatin, instead.
2013-09-27 | E-GEOD-42705 | biostudies-arrayexpress
Project description:U-2 OS (human osteosarcoma cell line) were treated with ZM447439 (an aurora kinase inhibitor), SB202190 (a p38 inhibitor) or ZM447439+SB202190 and resulting changes in gene expression were profiled.
2017-07-01 | E-MTAB-1210 | biostudies-arrayexpress
Project description:In this study, we sought to understand the impact of CHD1 on sensitivity to Aurora A inhibitors in prostate and other cancers and underlying mechanisms
2023-10-16 | GSE186633 | GEO
Project description:Aurora B, together with IN-box, the C-terminal part of INCENP, forms an enzymatic complex that ensures faithful cell division. The [Aurora B/IN-box] complex is activated by autophosphorylation in the Aurora B activation loop and in IN-box, but it is not clear how these phosphorylations activate the enzyme. We used a combination of experimental and computational studies to investigate the effects of phosphorylation on the molecular dynamics and structure of [Aurora B/IN-box]. In addition, we generated partially phosphorylated intermediates to analyze the contribution of each phosphorylation independently. We found that the dynamics of Aurora and IN-box are interconnected, and IN-box plays both positive and negative regulatory roles depending on the phosphorylation status of the enzyme complex. Phosphorylation in the activation loop of Aurora B occurs intramolecularly and prepares the enzyme complex for activation, but two phosphorylated sites are synergistically responsible for full enzyme activity.
2023-05-31 | PXD038935 | Pride
Project description:Mitotic catastrophe (MC) is an important mechanism to remove cells that become polyploid or aneuploid, as an oncosuppressive mechanism. Previous studies have demonstrated that the activation and catalytic function of caspase-2 is a key step in MC, to trigger apoptosis and/or cell cycle arrest of such defective cells. However, the molecular mechanisms that regulate caspase-2 activation and its function are unclear. Here we show that Aurora kinase B (AURKB), a key mitotic kinase, phosphorylates caspase-2 at a highly conserved residue S384 and inhibits its catalytic activity and function. We identified six new phosphorylation sites in caspase-2 and further demonstrated that phosphorylation at S384 blocks caspase-2 catalytic activity and apoptosis function in response to mitotic insults, without affecting caspase-2 dimerisation. Moreover, molecular modelling suggests that phosphorylation at S384 may affect substrate binding by caspase-2. We propose that caspase-2 S384 phosphorylation by AURKB is a key mechanism that controls caspase-2 activation during mitosis.
2021-09-09 | PXD017866 | Pride
Project description:Dynamic phosphorylation of FOXA1 by Aurora B guides post-mitotic gene reactivation
| PRJNA1142976 | ENA
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