Similar Datasets
Project description:To determine specificity of Aurora-A PROTAC (JB170), MV4-11 cells were labeled with medium containing different stable isotopes (SILAC), treated them with JB170 or Alisertib and subsequently compared their protein content to untreated cells by quantitative mass spectrometry.
2020-09-28 | PXD017342 | Pride
Project description:Targeted protein degradation reveals non-catalytic function of Aurora A kinase
| PRJNA595152 | ENA
Project description:The mitotic kinase AURORA-A is essential for cell cycle progression and is considered a priority cancer target. Although the catalytic activity of AURORA-A is essential for its mitotic function, recent reports indicate an additional non-catalytic function, which is difficult to target by conventional small molecules. We therefore developed a series of chemical degraders (PROTACs) by connecting a clinical kinase inhibitor of AURORA-A to E3 ligase-binding molecules (for example, thalidomide). One degrader induced rapid, durable and highly specific degradation of AURORA-A. In addition, we found that the degrader complex was stabilized by cooperative binding between AURORA-A and CEREBLON. Degrader-mediated AURORA-A depletion caused an S-phase defect, which is not the cell cycle effect observed upon kinase inhibition, supporting an important non-catalytic function of AURORA-A during DNA replication. AURORA-A degradation induced rampant apoptosis in cancer cell lines and thus represents a versatile starting point for developing new therapeutics to counter AURORA-A function in cancer.
| S-EPMC7610535 | biostudies-literature
Project description:To determine interactors of Aurora-A, HA tagged Aurora-A was immunoprecipitated from MV4-11 cells stably expressing HA tagged Aurora-A wild type and compared to MV4-11 cells expressing empty vector.
2020-09-28 | PXD019684 | Pride
Project description:The family of AURORA kinases is essential for cell cycle progression and dysregulation of AURORA-A in cancer led to a large number of clinical and pre-clinical inhibitors. However, ATP competitive AURORA-A inhibitors usually do not target non-catalytic functions that have also been identified as mechanisms promoting tumorigenesis. To target non-catalytic as well as catalytic functions, we developed a series of PROTACs (PROteolysis targeting chimeras) based on the selective AURORA-A kinase inhibitor MK-5108 (VX-689) and the CEREBLON E3-ligase ligands. The most potent PROTAC, JB301, had good physicochemical properties and cell penetration resulting in degradation of AURORA-A in leukemic cells at single digit nM concentration. In the presented datasets, we determined the intracellular degradation specificity of the AURKA PROTAC JB300. We therefore treated MV4-11 cells with JB300 and the corresponding ligand MK-5108, or DMSO and quantified the induced degradation using a label free approach.
2023-09-14 | PXD033239 | Pride
Project description:Aurora B is a mitotic checkpoint kinase that plays a pivotal role in the cell cycle, ensuring correct chromosome segregation and normal progression through mitosis. Aurora B is overexpressed in many types of human cancers, which has made it an attractive target for cancer therapies. Tumor suppressor p53 is a genome guardian and important negative regulator of the cell cycle. Whether Aurora B and p53 are coordinately regulated during the cell cycle is not known. We report that Aurora B directly interacts with p53 at different subcellular localizations and during different phases of the cell cycle (for instance, at the nucleus in interphase and the centromeres in prometaphase of mitosis). We show that Aurora B phosphorylates p53 at S183, T211, and S215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and PUMA). Pharmacologic inhibition of Aurora B in cancer cells with WT p53 increased p53 protein level and expression of p53 target genes to inhibit tumor growth. Together, these results define a mechanism of p53 inactivation during the cell cycle and imply that oncogenic hyperactivation or overexpression of Aurora B may compromise the tumor suppressor function of p53. We have elucidated the antineoplastic mechanism for Aurora B kinase inhibitors in cancer cells with WT p53.
| S-EPMC3386093 | biostudies-literature
Project description:Aurora kinases are central regulators of mitotic-spindle assembly, chromosome segregation and cytokinesis. Aurora B is a member of the chromosomal passenger complex (CPC) with crucial functions in regulation of the attachment of kinetochores to microtubules and in cytokinesis. We report here that Aurora B contains a conserved SUMO modification motif within its kinase domain. Aurora B can bind SUMO peptides in vitro when bound to the IN-box domain of its CPC partner INCENP. Mutation of Lys207 to arginine (Aurora B(K207R)) impairs the formation of conjugates of Aurora B and SUMO in vivo. Expression of the SUMO-null form of Aurora B results in abnormal chromosome segregation and cytokinesis failure and it is not able to rescue mitotic defects in Aurora-B-knockout cells. These defects are accompanied by increased levels of the CPC on chromosome arms and defective centromeric function, as detected by decreased phosphorylation of the Aurora-B substrate CENP-A. The Aurora-B(K207R) mutant does not display reduced kinase activity, suggesting that functional defects are probably a consequence of the altered localization, rather than decreased intrinsic kinase activity. These data suggest that SUMOylation of Aurora B modulates its function, possibly by mediating the extraction of CPC complexes from chromosome arms during prometaphase.
| S-EPMC2915883 | biostudies-literature
Project description:To study the senescence gene signatures in the cells, which were genetic SMARCB1 depleted or treated with aurora kinase inhibitors or etoposide, we performed next generation RNA sequencing on these cell, and 'FRIDMAN_SENESCENCE_UP' geneset was used to determine the enrichment of senescence-related genes. The RNA sequencing results include (1) A375 cells and SMARCB1 depleted counterparts. (2) A549 cells and aurora kinase inhibitor (Alisertib, barasertib or tozasertib) or etoposide treated counterparts.
2017-09-21 | GSE102639 | GEO
Project description:CD36 impacts the expression of genes in MV4-11 cells
2024-05-14 | GSE209783 | GEO
Project description:Our gene set analysis of MV4-11-R versus MV4-11 indicated decreased depolarization of mitochondria and mitochondrial membrane, mitochondrial dysfunction and anti-apoptosis as other top ranked molecular or cellular functions of differential gene sets. expression of most genes encoding glycolytic enzymes was up-regulated in MV4-11-R cells we revealed a metabolic alteration in sorafenib-resistant cell lines with mitochondrial respiration deficiency, leading to substantial decrease of mitochondria-derived ATP generation and a significant increase in glycolytic activity to maintain sufficient ATP production. Our study revealed a metabolic signature of sorafenib resistance and indicated that increase of glycolytic activity including upregulation of major glycolytic enzymes may be viewed as a marker for early detection of sorafenib resistance in AML patients with FLT3/ITD mutation and glycolytic inhibitors warrant further investigation as alternative therapeutic agents for sorafenib-resistant cells Sorafenib resistant cells MV411-R VS. parental MV4-11 cells. Biological replicates: 3 control replicates, 3 treated replicates.
2016-08-01 | E-GEOD-74666 | biostudies-arrayexpress