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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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A novel post-translational mechanism controlling the oncogenic activity of c-Myc is enhanced in poor outcome breast cancer

ABSTRACT: Examination of Pin1-regulated Myc target genes in a human breast epithelial cell line. Two samples: control GFP-expressing MCF10A-Myc cells and Pin1-expressing MCF10A-Myc cells.

ORGANISM(S): Homo sapiens

SUBMITTER: Rosalie Sears

PROVIDER: E-GEOD-33776 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Pin1 regulates the dynamics of c-Myc DNA binding to facilitate target gene regulation and oncogenesis.

Farrell Amy S AS Pelz Carl C Wang Xiaoyan X Daniel Colin J CJ Wang Zhiping Z Su Yulong Y Janghorban Mahnaz M Zhang Xiaoli X Morgan Charlie C Impey Soren S Sears Rosalie C RC

Molecular and cellular biology 20130528 15

The Myc oncoprotein is considered a master regulator of gene transcription by virtue of its ability to modulate the expression of a large percentage of all genes. However, mechanisms that direct Myc's recruitment to DNA and target gene selection to elicit specific cellular functions have not been well elucidated. Here, we report that the Pin1 prolyl isomerase enhances recruitment of serine 62-phosphorylated Myc and its coactivators to select promoters during gene activation, followed by promotin ...[more]

PMID: 23716601

Similar Datasets

Pin1 is required for sustained B cell proliferation upon oncogenic activation of Myc

Project description:The c-myc proto-oncogene is activated by translocation in Burkitt's lymphoma and substitutions in codon 58 stabilize the Myc protein or augment its oncogenic potential. In wild-type Myc, phosphorylation of Ser 62 and Thr 58 provide a landing pad for the peptidyl prolyl-isomerase Pin1, which in turn promotes Ser 62 dephosphorylation and Myc degradation. However, the role of Pin1 in Myc-induced lymphomagenesis remains unknown. We show here that genetic ablation of Pin1 reduces lymphomagenesis in EÂµ-myc transgenic mice. In both Pin1-deficient B-cells and MEFs, the proliferative response to Myc was selectively impaired, with no alterations in Myc-induced apoptosis or mitogen-induced cell cycle entry. This proliferative defect wasn't attributable to alterations in either Ser 62 phosphorylation or Myc-regulated transcription, but to the indirect activation of an Arf-p53 dependent cytostatic response. Pin1 silencing in lymphomas retarded disease progression in mice, making Pin1 an attractive therapeutic target in Myc-driven tumors. RNAseq samples of Pin1+/+ control (n=4), Pin1 -/- control (n=2), Pin1+/+ EÂµ-myc pre-tumoral (n=3), and Pin1-/- EÂµ-myc pre-tumoral (n=4) B cells.

2016-06-14 | E-GEOD-77482 | biostudies-arrayexpress

Pin1 is required for sustained B cell proliferation upon oncogenic activation of Myc

Project description:The c-myc proto-oncogene is activated by translocation in Burkitt's lymphoma and substitutions in codon 58 stabilize the Myc protein or augment its oncogenic potential. In wild-type Myc, phosphorylation of Ser 62 and Thr 58 provide a landing pad for the peptidyl prolyl-isomerase Pin1, which in turn promotes Ser 62 dephosphorylation and Myc degradation. However, the role of Pin1 in Myc-induced lymphomagenesis remains unknown. We show here that genetic ablation of Pin1 reduces lymphomagenesis in Eµ-myc transgenic mice. In both Pin1-deficient B-cells and MEFs, the proliferative response to Myc was selectively impaired, with no alterations in Myc-induced apoptosis or mitogen-induced cell cycle entry. This proliferative defect wasn't attributable to alterations in either Ser 62 phosphorylation or Myc-regulated transcription, but to the indirect activation of an Arf-p53 dependent cytostatic response. Pin1 silencing in lymphomas retarded disease progression in mice, making Pin1 an attractive therapeutic target in Myc-driven tumors.

2016-06-14 | GSE77482 | GEO

Genome-wide mapping of Nr5a2 in mouse embryonic stem cells

Project description:Nr5a2 (also known as liver receptor homolog-1, Lrh-1) has been shown to bind both the proximal enhancer and proximal promoter regions of Pou5f1 and regulate Pou5f1 in the epiblast stage of mouse embryonic development (Gu et al., 2005). Nr5a2-null embryos display a loss of Oct4 expression in the epiblasts (Gu et al., 2005) and die between E6.5 and E7.5 (Gu et al., 2005; Pare et al., 2004). To identify the targets of Nr5a2, we generated a stable ES cell-line that expresses HA-tagged Nr5a2. Anti-HA antibody was used to immunoprecipitate HA-Nr5a2 for ChIP-seq analysis. Keywords: Transcription factor binding sites To identify the binding sites of Nr5a2, we generated a stable ES cell-line that expresses HA-tagged Nr5a2. Anti-HA antibody was used to immunoprecipitate HA-Nr5a2.

2010-01-22 | E-GEOD-19019 | biostudies-arrayexpress

Genome-wide mapping of Eset-binding sites and H3K9me3 state in mouse embryonic stem cells

Project description:The histone H3 lysine 9 (H3K9) methyltransferase Eset is an epigenetic regulator critical for the development of the inner cell mass (ICM). Although ICM-derived embryonic stem (ES) cells are normally unable to contribute to the trophectoderm (TE) in blastocysts, we find that depletion of Eset by shRNAs leads to differentiation with the formation of trophoblast-like cells and induction of trophoblast-associated gene expression. Using ChIP-seq analyses, we identified Eset target genes with Eset-dependent H3K9 trimethylation. We confirmed that genes that are preferentially expressed in the TE (Tcfap2a and Cdx2) are bound and repressed by Eset. Single cell PCR analysis shows that the expression of Cdx2 and Tcfap2a is also induced in Eset-depleted morula cells. Importantly, Eset-depleted cells can incorporate into the TE of a blastocyst and subsequently placental tissues. Co-immunoprecipitation and ChIP assays further demonstrates that Eset interacts with Oct4, which in turn recruits Eset to silence these trophoblast-associated genes. Our result suggests that Eset restricts the extraembryonic trophoblast lineage potential of pluripotent cells and links an epigenetic regulator to key cell fate decision through a pluripotency factor. Keywords: Epigenetics Examine Eset-binding sites and compare the H3K9me3 state between Eset knockdown mouse ES cells and control knockdown mouse ES cells.

2009-11-04 | E-GEOD-17642 | biostudies-arrayexpress

Mapping of transcription factor binding sites in mouse embryonic stem cells

Project description:Transcription factors and their specific interactions with targets are crucial in specifying gene expression programs. To gain insights into the transcriptional regulatory networks in embryonic stem cells, we use chromatin immunoprecipitation coupled to ultra-high-throughput DNA sequencing (ChIP-seq) to map the locations of thirteen sequence specific transcription factors (Nanog, Oct4, STAT3, Smad1, Sox2, Zfx, c-Myc, n-Myc, Klf4, Esrrb, Tcfcp2l1, E2f1 and CTCF) and two transcription regulators (p300 and Suz12). These factors are known to play different roles in ES cell biology as components of the LIF and BMP signaling pathways, self-renewal regulators and key reprogramming factors. Our study provides insights into the integration of the signaling pathways to the ES cell-specific transcription circuitries. Intriguingly, we find specific genomic regions extensively targeted by different transcription factors. Collectively, the comprehensive mapping of transcription factor binding sites identifies important features of the transcriptional regulatory networks that define ES cell identity. Keywords: Transcription factor binding sites in undifferentiated mouse embryonic stem cells ChIP-enriched DNA from pooled ChIP samples were analyzed by Solexa sequencing.

2008-06-12 | E-GEOD-11431 | biostudies-arrayexpress

A novel post-translational mechanism controlling the oncogenic activity of c-Myc is enhanced in poor outcome breast cancer

Project description:Examination of Pin1-regulated Myc target genes in a human breast epithelial cell line.

2014-05-28 | GSE33776 | GEO

Sulfopin, a covalent inhibitor of Pin1, blocks Myc-driven tumors in vivo

Project description:The peptidyl-prolyl isomerase, Pin1, is exploited in cancer to activate oncogenes and inactivate tumor suppressors. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to identify covalent inhibitors targeting Pin1’s active site Cys113, leading to the development of Sulfopin, a nanomolar Pin1 inhibitor. Sulfopin is highly selective, as validated by two independent chemoproteomics methods, achieves potent cellular and in vivo target engagement, and phenocopies Pin1 genetic knockout. Pin1 inhibition had only a modest effect on cancer cell line viability. Still, Sulfopin induced downregulation of c-Myc target genes, reduced tumor progression and conferred survival benefit in murine and zebrafish models of MYCN-driven neuroblastoma, and in a murine model of pancreatic cancer. Our results demonstrate that Sulfopin is a suitable chemical probe for assessing Pin1-dependent pharmacology in cells and in vivo, and that Pin1 warrants further investigation as a potential cancer drug target.

2021-04-01 | GSE166786 | GEO

Effect of global MYC DNA binding due to loss of PIN1

Project description:The goal of this study was to determine the MYC binding difference between WT and PIN1 knockout mouse embryonic fibroblasts.

2018-11-20 | GSE109458 | GEO

Genome-wide mapping of Flag-Evi1 in SKOV-3 ovarian carcinoma cells

Project description:Discovery of Evi1 genomic occupancy and target genes ChIP-enriched DNA and input DNA were analyzed by Solexa sequencing.

2012-01-15 | E-GEOD-25210 | biostudies-arrayexpress

Genome-wide characterization of the transcriptional program of Myc-dependent transformation, ChIP-chip

Project description:We profiled Myc binding in a normal breast cell-line (MCF10A) under basal conditions after ectopic expression of Myc. We showed that ectopic Myc expression increases tumour formation in vivo and in vitro. We then profiled genome-wide Myc binding using Agilent promoter arrays in MCF10A cells expressing wild-type and ectopic Myc. We show that Myc binds to a greater number of spots in wild-type than in Myc cells, but that some targets are unique to each condition. Keywords: ChIP-chip

2009-11-24 | GSE13749 | GEO

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