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Effect of T350 phosphorylation on gene repression activity of EZH2 in BJ cells

ABSTRACT: The Polycomb group (PcG) protein enhancer of zeste homolog 2 (EZH2) plays an essential role in histone methylation-mediated epigenetic gene silencing. We demonstrate that under physiological conditions, cyclin-dependent kinase 1 (CDK1) and 2 (CDK2) bind to and phosphorylate EZH2 at threonine 350 (T350) in an evolutionally conserved motif. T350 phosphorylation is required for EZH2 function in silencing of genes that promote differentiation and inhibit proliferation and migration. Blockage of T350 phosphorylation by generating a T350A mutation largely diminishes the global effect of EZH2 on gene silencing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE22427 | GEO | 2010/11/10

SECONDARY ACCESSION(S): PRJNA128549

REPOSITORIES: GEO

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Effect of T350 phosphorylation on gene repression activity of EZH2 in BJ cells

Project description:The Polycomb group (PcG) protein enhancer of zeste homolog 2 (EZH2) plays an essential role in histone methylation-mediated epigenetic gene silencing. We demonstrate that under physiological conditions, cyclin-dependent kinase 1 (CDK1) and 2 (CDK2) bind to and phosphorylate EZH2 at threonine 350 (T350) in an evolutionally conserved motif. T350 phosphorylation is required for EZH2 function in silencing of genes that promote differentiation and inhibit proliferation and migration. Blockage of T350 phosphorylation by generating a T350A mutation largely diminishes the global effect of EZH2 on gene silencing. Four experiments have been designed. BJ cells were transfected with si-Control, si-EZH2, si-EZH2 plus RNAi resistant lentivirus expressed EZH2, or si-EZH2 plus RNAi resistant lentivirus expressed T350A mutant for 60 hours. Each experiment was triplicated.

2010-11-10 | E-GEOD-22427 | biostudies-arrayexpress

Effects of T350 phospho- on gene repression activity of EZH2

2010-11-02 | GSE20433 | GEO

Effects of T350 phospho- on gene repression activity of EZH2

Project description:The Polycomb group (PcG) protein enhancer of zeste homolog 2 (EZH2) plays an essential role in histone methylation-mediated epigenetic gene silencing. We demonstrate that under physiological conditions, cyclin-dependent kinase 1 (CDK1) and 2 (CDK2) bind to and phosphorylate EZH2 at threonine 350 (T350) in an evolutionally conserved motif. T350 phosphorylation is required for EZH2 function in silencing of genes that promote differentiation and inhibit proliferation and migration. Blockage of T350 phosphorylation by generating a T350A mutation largely diminishes the global effect of EZH2 on gene silencing. Seven experiments have been designed. LNCaP cells were transfected with si-Control, si-EZH2, si-EZH2 plus RNAi resistant EZH2 plasmid, or si-EZH2 plus RNAi resistant T350A mutated EZH2 plsamid for 60 hours, or treated with DMSO, 5 uM TSA, or 10 uM Roscovitine for 24 hours. Two replicates per experiment.

2010-11-02 | E-GEOD-20433 | biostudies-arrayexpress

Genome-wide profiling analysis reveals annexin A6 is a novel EZH2 target gene involving gastric cellular proliferation

Project description:Polycomb repressive complexes (PRC) play a critical role during tumorigenesis and development. The histone methyltransferase Enhancer of Zeste homologue 2 (EZH2), as a core component of PRC2, is frequently overexpressed in a wide variety of cancers. EZH2-mediated gene silencing contributes to carcinogenesis. To further the understanding of the EZH2 biology in gastric cancer, here we performed transcriptome analyses and identified EZH2-responsive genes upon EZH2 knockdown by RNA-seq.

2015-11-07 | E-MTAB-3227 | biostudies-arrayexpress

CDK1 and CDK2 regulate NICD1 turnover and the periodicity of the segmentation clock

Project description:All vertebrates share a segmented body axis. Segments form from the rostral end of the presomitic mesoderm (PSM) with a periodicity that is regulated by the segmentation clock. The segmentation clock is a molecular oscillator that exhibits dynamic clock gene expression across the PSM with a periodicity that matches somite formation. Notch signalling is crucial to this process. Altering Notch intracellular domain (NICD) stability affects both the clock period and somite size. However, the mechanism by which NICD stability is regulated in this context is unclear. We identified a highly conserved site crucial for NICD recognition by the SCF E3 ligase, which targets NICD for degradation. We demonstrate both CDK1 and CDK2 can phosphorylate NICD in the domain where this crucial residue lies and that NICD levels vary in a cell cycle-dependent manner. Inhibiting CDK1 or CDK2 activity increases NICD levels both in vitro and in vivo, leading to a delay of clock gene oscillations and an increase in somite size.

2020-03-24 | PXD013038 | Pride

Regulation of Angiogenesis by EZH2

Project description:While VEGF-targeted therapies are showing promise in clinical studies, new angiogenesis targets are needed to make additional gains. Here, we show that increased Zeste homologue 2 (EZH2) expression in either tumor cells or in tumor vasculature is predictive of poor clinical outcome. The increase in endothelial EZH2 is a direct result of VEGF stimulation and indicates the presence of a paracrine circuit that promotes angiogenesis by methylating and silencing vasohibin 1 (VASH1). EZH2 silencing in the tumor-associated endothelial cells resulted in inhibition of angiogenesis mediated by reactivation of VASH1, and reduced ovarian cancer growth. Combined, these data provide a new understanding of the regulation of tumor angiogenesis and support the potential for targeting EZH2 as a novel therapeutic approach. Pre-clinical study, DNA microarray (Illumina HumanHT-12)

2010-10-12 | E-GEOD-20381 | biostudies-arrayexpress

miR101 overexpression vs. EZH2 RNAi

Project description:Transcriptional analysis of genes in SKBr3 cells. Enhancer of zeste homolog 2 (EZH2) is a mammalian histone methyltransferase that contributes to the epigenetic silencing of target genes and regulates the survival and metastasis of cancer cells. EZH2 is overexpressed in aggressive solid tumors by mechanisms that remain unclear. Here we show that the expression and function of EZH2 in cancer cell lines are inhibited by microRNA-101 (miR-101).

2009-04-28 | GSE13286 | GEO

Blocking immunosuppressive neutrophils deters pY696-EZH2-driven brain metastases

Project description:In brain metastatic cells, enhancer of zeste homologue 2 (EZH2) is highly expressed and phosphorylated at tyrosine-696 (pY696-EZH2) by nuclear-localized Src tyrosine kinase. Phosphorylation of EZH2 at Y696 changes its binding preference from histone H3 to RNA polymerase II, which consequently switches EZH2’s function from a methyltransferase to a transcription factor that increases c-Jun expression. c-Jun upregulates pro-tumorigenic inflammatory cytokines, including granulocyte-colony stimulating factor (G-CSF), which recruits Arg1-positive and PD-L1-positive immunosuppressive neutrophils into the brain to drive metastasis outgrowth.

2021-11-14 | GSE188640 | GEO

Localized phosphorylation of RNA Polymerase II by G1 cyclin-Cdk promotes cell cycle entry

Project description:The cell cycle is thought to be initiated by cyclin-dependent kinases (Cdk) inactivating transcriptional inhibitors of cell cycle gene-expression. In budding yeast, the G1 cyclin Cln3-Cdk1 complex is thought to directly phosphorylate Whi5, thereby releasing the transcription factor SBF and committing cells to division. Here, we report that Cln3-Cdk1 does not phosphorylate Whi5, but instead phosphorylates the RNA Polymerase II subunit Rpb1’s C-terminal domain (CTD) on S5 of its heptapeptide repeats. Cln3-Cdk1 binds SBF-regulated promoters(8) and Cln3’s function can be performed by the canonical S5 kinase Ccl1-Kin28 when synthetically recruited to SBF. Thus, Cln3-Cdk1 triggers cell division by phosphorylating Rpb1 at SBF-regulated promoters to promote transcription. Our findings blur the distinction between cell cycle and transcriptional Cdks to highlight the ancient relationship between these processes.

2021-12-01 | GSE169271 | GEO

Global altered gene expression in triple-negative breast cancer tumor samples treated with CDK2 and EZH2 inhibitors

Project description:Triple-negative breast cancer cell line SUM-149 xenograft mouse model was treated with CDK2 inhibitor (dinaciclib) and EZH2 inhibitor (EPZ6438) for 10 days to examine global transcriptome alternations by RNAseq. Expression levels of more than 801 and 741 gene were altered by CDK2 inhibitor and EZH2 inhibitor treatment, respectively.Among differential changed genes induced by CDK2 inhibitor and EZH2 inhibitor, we defined top 109 common up- and down-regulated gene sets in the inhibitor-treated tumors.

2019-06-05 | GSE132194 | GEO

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