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Comparison between Nestin+ and Nestin- Ptch1 deficient GNPs

ABSTRACT: The intermediate filament protein Nestin serves as a biomarker for stem cells and has been used to identify subsets of cancer stem-like cells. However, the mechanistic contributions of Nestin to cancer pathogenesis are not understood. Here we report that Nestin binds the hedgehog pathway transcription factor Gli3 to mediate the development of medulloblastomas of the hedgehog subtype. In a mouse model system, Nestin levels increased progressively during medulloblastoma formation resulting in enhanced tumor growth. Conversely, loss of Nestin dramatically inhibited proliferation and promoted differentiation. Mechanistic investigations revealed that the tumor-promoting effects of Nestin were mediated by binding to Gli3, a zinc finger transcription factor that negatively regulates hedgehog signaling. Nestin binding to Gli3 blocked Gli3 phosphorylation and its subsequent proteolytic processing, thereby abrogating its ability to negatively regulate the hedgehog pathway. Our findings show how Nestin drives hedgehog pathway-driven cancers and uncover in Gli3 a therapeutic target to treat these malignancies.

ORGANISM(S): Mus musculus

PROVIDER: GSE84392 | GEO | 2016/08/09

SECONDARY ACCESSION(S): PRJNA338113

REPOSITORIES: GEO

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Comparison between Nestin+ and Nestin- Ptch1 deficient GNPs

Project description:The intermediate filament protein Nestin serves as a biomarker for stem cells and has been used to identify subsets of cancer stem-like cells. However, the mechanistic contributions of Nestin to cancer pathogenesis are not understood. Here we report that Nestin binds the hedgehog pathway transcription factor Gli3 to mediate the development of medulloblastomas of the hedgehog subtype. In a mouse model system, Nestin levels increased progressively during medulloblastoma formation resulting in enhanced tumor growth. Conversely, loss of Nestin dramatically inhibited proliferation and promoted differentiation. Mechanistic investigations revealed that the tumor-promoting effects of Nestin were mediated by binding to Gli3, a zinc finger transcription factor that negatively regulates hedgehog signaling. Nestin binding to Gli3 blocked Gli3 phosphorylation and its subsequent proteolytic processing, thereby abrogating its ability to negatively regulate the hedgehog pathway. Our findings show how Nestin drives hedgehog pathway-driven cancers and uncover in Gli3 a therapeutic target to treat these malignancies. Nestin+ and Nestin- GNPs (granule neuron precursors) were purified from Nestin-CFP/Math1-Cre/Ptch1-loxp cerebella at postnatal day 4 by FACs, and total RNA from these two cell populations were extracted, and then labeled and hybridized to Affymetrix Mouse Genome 430 2.0 arrays.

2016-08-09 | E-GEOD-84392 | biostudies-arrayexpress

Regulation of Ptch1 expression in the limb

Project description:Ptch1 is a critical negative feedback regulator of the Hedgehog signaling and is upregulated in response to pathway activation. How tissue specific responses are mediated remains unknown. Here, we performed ChIP-seq analysis for epitope-tagged endogenous Gli3 protein to identify limb-specific binding regions within the 500 kb region surrounding Ptch1. ChIP was carried out using an endogenously FLAG-tagged Gli3 protein.

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Regulation of Ptch1 expression in the limb

2014-07-03 | GSE52939 | GEO

Ptch1+/- Nos2-/- medulloblastomas

Project description:This SuperSeries is composed of the following subset Series: GSE29192: Implication of Nos2 inactivation on the transcriptome of developing cerebellum and Ptch1+/- medulloblastomas (mRNA) GSE29199: Implication of Nos2 inactivation on genomic changes in Ptch1+/- medulloblastomas (array-CGH) Refer to individual Series

2011-12-01 | E-GEOD-29201 | biostudies-arrayexpress

The transcription factor Gli3 promotes B cell development in the fetal liver through repression of Shh

Project description:Before birth B-cells develop in the fetal liver (FL). Here we show that Gli3 activity in the FL stroma is required for B-cell development. In the Gli3-deficient FL B-cell development was reduced at multiple stages, whereas the Sonic hedgehog (Shh)-deficient FL showed increased B-cell development, and Gli3 functioned to repress Shh transcription. Use of a transgenic Hedgehog (Hh)-reporter mouse showed that Shh signals directly to developing B-cells, and that Hh pathway activation was increased in developing B-cells from Gli3-deficient fetal liver. RNAsequencing confirmed that Hh-mediated transcription is increased in B-lineage cells from Gli3-deficient FL, and showed that these cells expressed reduced levels of B-lineage transcription factors and BCR/pre-BCR-signalling genes. We showed that expression of the master regulators of B-cell development, Ebf1 and Pax5, is reduced in developing B-cells from Gli3-deficient FL and increased in Shh-deficient FL, and that in vitro Shh-treatment or neutralisation can repress or induce their expression respectively.

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Quantitative proteomics links the intermediate filament nestin to vemurafenib resistance in melanoma cell lines

Project description:Targeted inhibition of mutated kinases using selective MAP kinase inhibitors in malignant melanoma often results in temporary improvement of the metastatic disease followed by rapid development of resistance. To gain insights in molecular processes that govern resistance, we performed SILAC-based quantitative proteomics profiling of vemurafenib-resistant and -sensitive melanoma cells. Among downregulated proteins in vemurafenib-resistant cell lines we detected multiple proteins involved in cytoskeletal organization and signaling, including the intermediate filament nestin, which was one of the most down-regulated proteins. Previous studies showed that nestin is expressed in various types of solid tumors and its abundance correlates with malignant phenotype of transformed cells. However, the role of nestin in cancer cells with regard to acquired resistance is still poorly understood. We performed CRISPR/Cas9 knockout of the nestin gene (NES) in vemurafenib-sensitive cells and showed that loss of nestin leads to increased cellular proliferation and colony formation upon treatment with BRAF and MEK inhibitors. Moreover, nestin depletion led to increased invasiveness and metalloproteinase activity similar to resistant phenotype of melanoma cells. Finally, phosphoproteome analysis revealed that nestin depletion influenced signaling through integrin and PI3K-Akt-mTOR pathways and led to increased focal adhesion kinase expression and phosphorylation. Taken together, our results reveal that nestin is associated with acquired vemurafenib resistance in melanoma cell lines.

2019-05-14 | PXD010683 | Pride

Sonic Hedgehog subgroup medulloblastomas

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RNA-seq and ChIP-seq identification of unique and overlapping targets of GLI transcription factors in melanoma cell lines

Project description:Despite significant progress in therapy, melanoma is still the most lethal form of skin cancer, with a rising incidence worldwide. Little is known about the impact of deregulated Hedgehog-GLI (HH-GLI) signalling pathway in the progression of this disease. Based on previous research, we hypothesized that in melanoma activation of HH-GLI signaling pathway is non- canonical due to its crosstalk with MAPK signaling pathway, which is the most deregulated pathway in melanoma. In order to investigate the link between the two pathways and to find novel GLI transcriptional targets that could be considered for potential combination therapy, we performed RNA sequencing on three melanoma cell lines with overexpressed GLI1, GLI2 and GLI3 and combined them with results of ChIP sequencing on endogenous GLI1, GLI2 and GLI3 proteins on the same cell lines. RNA-seq revealed a total of 808 DEGs for GLI1, 941 DEGs for GLI2 and 58 DEGs for GLI3. ChIP-seq identified 527 genes that contained GLI1 binding sites in their promoters, 1103 for GLI2 and 553 for GLI3. After combining these results, 21 targets were selected for validation by qPCR. Fifteen of these targets were validated in the tested cell lines, 6 of which were detected by both RNA-seq and ChIP-seq.

2023-01-01 | E-MTAB-11936 | biostudies-arrayexpress

RNAseq for Nestin+ bone marrow stromal cells in normal and MLL-AF9 mice

Project description:Cumulative evidence points out to the importance of the bone microenvironment for leukaemic development. Our preliminary results show that bone marrow stem cells, identified by the expression of the intermediate filament protein nestin (Nestin+ cells), provide support and chemoresistance to leukaemic cells. The rationale for these experiments is that leukaemic/Nestin+ cells crosstalk might regulate Nestin+ cells genetic profile to become more supportive elements for leukaemia. Nestin expression level distinguish two different Nestin+ populations, which seem to possess distint characteristics. Therefore, we would like to separately study high-expressing (Nestin high) and low-expressing Nestin cells (Nestin low). From our in vitro results, Nestin+ cells seem to be providing detoxifying tools to leukaemic cells such as antioxidant aminoacids and enzymes. The aim of the project is to identify pathways and genes differentially regulated in Nestin+ high and/or low cells in a leukaemic background.

2020-11-24 | GSE140135 | GEO

cis-Regulatory analysis of Ptch1

Project description:Ptch1 is the primary receptor for Hedgehog ligands and functions as a negative regulator of the pathway. Ptch1 is upregulated in response to pathway activation and is a direct target of the Gli family of transcription factors that act as the downstream effectors of the pathwat. The goal of this study was to identify tissue specific Gli2 inputs to Ptch1 during development. Additionally, we assessed the prevalence of the repressive chromatin mark (H3K27me3) during directed differentiated of embryonic stem cells into neural progenitors.

2016-06-08 | GSE71199 | GEO

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