Effect of knockdown Aurora kinase A（AURKA） on gene expression in LX2 cells.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA909202 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22547400_1.fastq.gz | Fastqsanger.gz | |||
| SRR22547400_2.fastq.gz | Fastqsanger.gz | |||
| SRR22547401_1.fastq.gz | Fastqsanger.gz | |||
| SRR22547401_2.fastq.gz | Fastqsanger.gz | |||
| SRR22547402_1.fastq.gz | Fastqsanger.gz |
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Project description:We performed gene expression profiling analysis using data obtained from RNA-seq of LX2 cells treated with siRNA of AURKA or siNC.
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Project description:CXCR7, an atypical chemokine receptor (ACKR3), is up-regulated in NEPC, and its expression is associated with molecular markers of NEPC and cell proliferation. Transcriptomic analyses revealed a major role of CXCR7 in regulating downstream genes involved in the cell cycle and mitotic spindle. Membrane-bound CXCR7 is known to recruit β-arrestin (ARRB2), and the complex internalizes into clathrin-coated vesicles where they act as a scaffold for cytoplasmic kinase assembly and substrate activation. We identify Aurora Kinase A (AURKA) as a top candidate that is binding to and activated by CXCR7-ARRB2. Immunofluorescence confocal microscopy detected high-density CXCR7, ARRB2, and AURKA in the pericentrosomal area with focal staining of ARRB2 and ARUKA at centrosomes. Mass spectrometry showed that CXCR7 interacts with many proteins associated with intracellular vesicles, microtubules, and Golgi apparatus. CXCR7-ARRB2-containing vesicles traffic along the microtubules to the perinuclear Golgi apparatus, where CXCR7-ARRB2 interacts with AURKA to promote its activation and cell growth. Finally, we showed that pharmacological inhibitors of AURKA abolish CXCR7-driven tumor growth. Our study reveals CXCR7-mediated activation of AURKA and establishes CXCR7 and its downstream kinases as critical targets for therapeutic intervention in CRPC or NEPC patients.
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Project description:Graft versus host disease (GVHD) is the most common complication of hematopoietic stem cell transplant (HCT). However, our understanding of the molecular pathways that cause this disease remains incomplete, leading to inadequate treatment strategies. To address this, we measured the gene expression profile of non-human primate (NHP) T cells during acute GVHD (GSE73723). Within these profiles we discovered potentially druggable targets not previously implicated in GVHD, prominently including aurora kinase A (AURKA). In this study, we performed a planned comparison of AURKA gene expression in HCT-recipients with clinical GVHD and compared it to expression in HCT-recipients without clinical GVHD.
2015-11-29 | GSE73809 | GEO
Project description:Illumina Beadchip array analyses of mouse embryonic stem cell gene expression profiles in the presence of or upon knockdown of Aurka. An ES complementation 'rescue' system was employed to measure the effects of knockdown (minus Dox). Aurka was rescued to wildtype levels in the presence of Dox (plus Dox). A control rescue ES cell line, with a Luciferase-targeting shRNA, was also assessed. Total of 12 samples; Aurka_R (+/-Dox) and Control_R (+/-Dox); all performed in triplicates
2012-05-29 | E-GEOD-23541 | biostudies-arrayexpress
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.
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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:Illumina Beadchip array analyses of mouse embryonic stem cell gene expression profiles in the presence of or upon knockdown of Aurka. An ES complementation 'rescue' system was employed to measure the effects of knockdown (minus Dox). Aurka was rescued to wildtype levels in the presence of Dox (plus Dox). A control rescue ES cell line, with a Luciferase-targeting shRNA, was also assessed.
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Project description:Genetic alterations that activate protein kinase A (PKA) signaling are found across many tumor types, but their downstream oncogenic mechanisms are poorly understood. We used global phosphoproteomics and kinome activity profiling to map the conserved signaling outputs driven by diverse genetic changes that activate PKA in cancer. We define two consensus networks of effectors downstream of PKA in cancer models including melanoma and fibrolamellar carcinoma [FLC]. One is centered on RAS/MAPK components and a second involves Aurora Kinase A (AURKA). We find that AURKA stabilizes c-MYC and n-MYC protein levels and expression programs in PKA-dependent tumor models, in part via a positive feedback loop mediated by the oncogenic kinase PIM2. This process can be suppressed by conformation-disrupting AURKA inhibitors such as CD-532. Our findings elucidate two independent mechanisms of PKA-driven tumor cell growth and designate drug targets for study in FLC and other PKA-dependent malignancies.
2023-02-09 | PXD025508 | Pride
Project description:Aurora kinase A (AURKA) is a well-established target in neuroblastoma (NB) due to both its catalytic functions during mitosis and its kinase-independent functions, including stabilization of the key oncoprotein MYCN. We present a structure-activity relationship (SAR) study of MK-5108-derived PROTACs against AURKA by exploring different linker lengths and exit vectors on the thalidomide moiety. PROTAC SK2188 induces the most potent AURKA degradation (DC50,24h 3.9 nM, Dmax,24h 89%) and shows an excellent binding and degradation selectivity profile. Treatment of NGP neuroblastoma cells with SK2188 induced concomitant MYCN degradation, high replication stress/DNA damage levels and apoptosis. Moreover, SK2188 significantly outperforms the parent inhibitor MK-5108 in a cell proliferation screen and patient-derived organoids. Furthermore, altering the attachment point of the PEG linker to the 5-position of thalidomide allowed us to identify a potent AURKA degrader with a linker as short as 2 PEG units. With this, our SAR-study provides interesting lead structures for further optimization and validation of AURKA degradation as a potential therapeutic strategy in neuroblastoma.
2023-02-27 | PXD040389 | Pride
Project description:Aurora kinase A (AURKA) is a well-established target in neuroblastoma (NB) due to both its catalytic functions during mitosis and its kinase-independent functions, including stabilization of the key oncoprotein MYCN. We present a structure-activity relationship (SAR) study of MK-5108-derived PROTACs against AURKA by exploring different linker lengths and exit vectors on the thalidomide moiety. PROTAC SK2188 induces the most potent AURKA degradation (DC50,24h 3.9 nM, Dmax,24h 89%) and shows an excellent binding and degradation selectivity profile. Treatment of NGP neuroblastoma cells with SK2188 induced concomitant MYCN degradation, high replication stress/DNA damage levels and apoptosis. Moreover, SK2188 significantly outperforms the parent inhibitor MK-5108 in a cell proliferation screen and patient-derived organoids. Furthermore, altering the attachment point of the PEG linker to the 5-position of thalidomide allowed us to identify a potent AURKA degrader with a linker as short as 2 PEG units. With this, our SAR-study provides interesting lead structures for further optimization and validation of AURKA degradation as a potential therapeutic strategy in neuroblastoma
2023-02-27 | PXD040391 | Pride