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The CDK1/CDC14B-USP9X-WT1-IL-8 signalling pathway in mitotic survival

ABSTRACT: RNASeq was performed from mitotic U2OS osteosarcoma cells that were either unmutated or had been CRISPR/Cas9-modified to carry a homozygous alteration of the genomic region surrounding Serine 2563 of USP9X or that had been transfected with Ctrl or Wt1 siRNA.

PROVIDER: PRJEB36354 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR3865640_1.fastq.gz	Fastqsanger.gz
	ERR3865640_2.fastq.gz	Fastqsanger.gz
	ERR3865650_1.fastq.gz	Fastqsanger.gz
	ERR3865650_2.fastq.gz	Fastqsanger.gz
	ERR3865660_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Antagonistic activities of CDC14B and CDK1 on USP9X regulate WT1-dependent mitotic transcription and survival.

Project description:Regulation of mitosis secures cellular integrity and its failure critically contributes to the development, maintenance, and treatment resistance of cancer. In yeast, the dual phosphatase Cdc14 controls mitotic progression by antagonizing Cdk1-mediated protein phosphorylation. By contrast, specific mitotic functions of the mammalian Cdc14 orthologue CDC14B have remained largely elusive. Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis. We further demonstrate that WT1 functions as a mitotic transcription factor and specify CXCL8/IL-8 as a target gene of WT1 that conveys mitotic survival. Together, we describe a ubiquitin-dependent signaling pathway that directs a mitosis-specific transcription program to regulate mitotic survival.

| S-EPMC7063047 | biostudies-literature

Loss of Usp9x increases Wnt and Notch signaling in neural progenitors

Project description:Correct neural progenitor fate determination requires the coordination of extrinsic fate determinant signals with intrinsic responses. Post-translational modifications dynamically alter protein function and so are ideally situated to regulate development. Here we show that the deubiquitylaying enzyme, Usp9x modulates both intrinsic and extrinsic regulators of mouse neural progenitors. Nestin-cre mediated deletion of Usp9x from neural progenitors results in a transient disruption of cell adhesion and apical-basal polarity as well as the premature differentiation of intermediate neural progenitors. Ablation of Usp9x also significantly increased Î²-catenin protein levels, especially S33/S37/T41 phospho-Î²-catenin, and Wnt signalling. Usp9x was found to be part of the Î²-catenin destruction complex and loss of Usp9x affects destruction complex composition. Notch signalling was also increased in Usp9x ablated neural progenitors, coinciding with decreased Itch and Numb, and increased Notch intracellular domain protein levels. Usp9x co-localized and immunopreciptiated with Numb from neural progenitors suggesting it is required for Numb stabilisation. These data suggest Usp9x plays a role in coordinating intrinsic responses to extrinsic signals during neural development.

2017-08-18 | E-MTAB-4150 | biostudies-arrayexpress

USP9X phosphopeptide mapping - We previously identified the deubiquitylase USP9X as a G2/M-specific CDC14B interactor (PXD012732). The functional connection of these proteins has been further investigated by a quantitative comparison of USP9X phosphorylation in WT vs CDC14B-overexpressing HEK 293Tcells (ATCC® CRL-3216™). The approach identified USP9X serine 2563 as a specific CDC14B target. Phosphorylation at USP9XS2563 has been confirmed by in-house phosphospecific antibodies.

Project description:We previously identified the deubiquitylase USP9X as a G2/M-specific CDC14B interactor (PXD012732). The functional connection of these proteins has been further investigated by a quantitative comparison of USP9X phosphorylation in WT vs CDC14B-overexpressing HEK 293Tcells (ATCC® CRL-3216™). The approach identified USP9X serine 2563 as a specific CDC14B target. Phosphorylation at USP9XS2563 has been confirmed by in-house phosphospecific antibodies.

2020-03-25 | PXD012733 | Pride

The deubiquitinase Usp9x regulates PRC2-mediated chromatin reprogramming during mouse development

Project description:Pluripotent cells of the mammalian embryo undergo extensive chromatin rewiring to prepare for lineage commitment after implantation. Repressive H3K27me3, deposited by Polycomb Repressive Complex 2 (PRC2), is reallocated from large blankets in pre-implantation embryos to mark promoters of developmental genes. The regulation of the global redistribution of H3K27me3 is poorly understood. Here we report a post-translational mechanism that destabilizes PRC2 to constrict H3K27me3 during lineage commitment. Using an auxin-inducible degron system, we show that the deubiquitinase Usp9x is required for mouse embryonic stem (ES) cell self-renewal. Usp9x-high ES cells have high PRC2 levels and bear a chromatin and transcriptional signature of the pre-implantation embryo, whereas Usp9x-low ES cells resemble the post-implantation, gastrulating epiblast. We show that Usp9x interacts with, deubiquitinates and stabilizes PRC2. Deletion of Usp9x in post-implantation embryos results in the derepression of genes that normally gain H3K27me3 after gastrulation, followed by the appearance of morphological abnormalities at E9.5, pointing to a recurrent link between Usp9x and PRC2 during development. Usp9x is a marker of “stemness” and is mutated in various neurological disorders and cancers. Our results unveil a Usp9x-PRC2 regulatory axis that is critical at peri-implantation and may be redeployed in other stem cell fate transitions and disease states.

2021-01-25 | GSE146800 | GEO

Deubiquitinase USP9X regulates Wnt-signaling to control CNS vascular formation and barrier maintenance

Project description:Deubiquitinating enzymes play crucial roles in various cellular activities, yet their involvement in central nervous system (CNS) vascularization and barrier function remains elusive. Canonical Wnt signaling is essential for proper CNS vascularization and barrier maintenance. Using a loss-of-function screening for Wnt signaling activity, we identified ubiquitin-specific peptidase 9 X-linked (USP9X) as a key regulator in brain endothelial cells (BECs). Endothelium-specific Usp9x knockout reduces Wnt-signaling activity, compromising CNS vascularization and barrier function during development. Activation of Wnt signaling rescues these defects. Mechanistically, we uncovered β-catenin as a direct substrate of USP9X, with USP9X catalyzing K48 polyubiquitin chains to stabilize β-catenin. In pathological models of impaired CNS vascular barrier function, including an intracerebral hemorrhage model and an oxygen-induced retinopathy model, loss of Usp9x intensifies barrier disruption, accentuating defects. This finding implicates USP9X as a critical regulator of CNS vascularization and barrier function through Wnt signaling, offering insights into CNS disease implications.

2024-12-13 | GSE281249 | GEO

Deubiquitinase USP9X regulates Wnt-signaling to control CNS vascular formation and barrier maintenance [Human]

2024-12-13 | GSE281250 | GEO

USP9X stabilizes EWS-FLI1 to promote cancer cell growth in Ewing’s sarcoma

Project description:Ewing’s sarcoma (EWS) is a cancer of the bones or soft tissues in children and adolescents. EWS-FLI1 is a transcriptional factor and the key driver of EWS. To characterize the changes of downstream transcriptional profiles of EWS-FLI1 in A673 cells upon knockdown of EWS-FLI1 and deubiquitinase USP9X, RNA-seq was performed in A673 cells transfected with EWS-FLI1 esiRNA, USP9X esiRNA or GFP esiRNA as control. The data indicates that USP9X regulates transcriptional profiles of EWS through mediating EWS-FLI1.

2022-01-01 | GSE185429 | GEO

Nitric oxide prevents aortic valve calcification by S-nitrosylation of USP9X to activate NOTCH signaling

Project description:Calcific aortic valve disease (CAVD) is an increasingly prevalent condition and endothelial dysfunction is implicated in its etiology. We previously identified nitric oxide (NO) as a calcification inhibitor by its activation of NOTCH1, which is genetically linked to human CAVD. Here, we show that NO rescues calcification by a S-nitrosylation-mediated mechanism in porcine aortic valve interstitial cells (pAVICs) and single cell RNA-seq demonstrated regulation of NOTCH pathway by NO. A unbiased proteomic approach to identify S-nitrosylated proteins in valve cells found enrichment of the ubiquitin proteasome pathway and implicated S-nitrosylation of USP9X in NOTCH regulation during calcification. Furthermore, S-nitrosylated USP9X was shown to deubiquitinate and stabilize MIB1 for NOTCH1 activation. Consistent with this, genetic deletion of Usp9x in mice demonstrated aortic valve disease and human calcified aortic valves displayed reduced S-nitrosylation of USP9X. These results demonstrate a novel mechanism by which S-nitrosylation dependent regulation of ubiquitin-associated pathway prevents CAVD.

2020-12-22 | GSE161123 | GEO

WT1 Trio Peptide-vaccine for Rare Cancers

Project description:Interventions: A patient is vaccinated with Montanide ISA51-adjuvanted WT1 Trio cancer vaccine consisting of two WT1 CTL peptides (WT1-126 and WT1-235) and one WT1 HTL peptide (WT1-332) (2mg each) seven times at the interval of two weeks. Primary outcome(s): Induction of WT1-specific immune responses assessed by WT1-related tests such as WT1-DTH skin reaction and serum levels of WT1 peptide IgG autoantibody at 1M, 2M, and 3M of WT1 Trio vaccine. Study Design: Single arm Non-randomized

| 2638832 | ecrin-mdr-crc

MEF-mKras-WT1

Project description:K-ras is one of the most frequently mutated human oncogenes. Activation of K-ras can lead to either senescence or proliferation in primary cells. The precise mechanism governing these distinct outcomes remains unclear. Here we utilized a loss-of-function screen to assess the role of specific genes identified as potential key regulators of K-ras driven oncogenesis. Using this approach, we identify the transcription factor Wt1 as an inhibitor of senescence in primary cells expressing oncogenic K-ras. Deletion or suppression of Wt1 expression leads to senescence of primary cells expressing oncogenic K-ras under the control of the native promotor at physiological levels, but has no effect on cells expressing wild-type K-ras. Wt1 contributes to K-ras driven lung tumorigenesis in vivo and loss of Wt1 is specifically deleterious to human lung cancer cell lines that are dependent on oncogenic K-ras. Taken together, these observations reveal a novel role for Wt1 as a key regulator of the complex genetic network required for the oncogenic effect of the small GTPase K-ras. We compare the expression profiles of Wild type, K-ras mutant, Wt1-null, and double K-ras mutant/Wt1-null mouse embryonic fibroblasts (MEFs). The study provides insights into the transcriptional role of Wt1 in the context of oncogenic K-ras.

2010-03-01 | GSE15325 | GEO

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