Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Hes1 and Glucocorticoid Signaling in Bone Sarcoma Cells

ABSTRACT: To investigate the role of HES1 during glucocorticoid signaling in bone sarcoma cells (U2OS-GR cells) , we employed whole-genome microarray expressions in mRNA extracted from control U2OS-GR and Hes1-overexpressed U2OS-GR cells. RNA isolated from control U2OS-GR and Hes1-overexpressed U2OS-GR cells treated with VEH or Dexamethasone.

ORGANISM(S): Homo sapiens

SUBMITTER: NIEHS Microarray Core

PROVIDER: E-GEOD-52727 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

HES1 is a master regulator of glucocorticoid receptor-dependent gene expression.

Revollo Javier R JR Oakley Robert H RH Lu Nick Z NZ Kadmiel Mahita M Gandhavadi Maheer M Cidlowski John A JA

Science signaling 20131203 304

Hairy and enhancer of split-1 (HES1) is a basic helix-loop-helix transcription factor that is a key regulator of development and organogenesis. However, little is known about the role of HES1 after birth. Glucocorticoids, primary stress hormones that are essential for life, regulate numerous homeostatic processes that permit vertebrates to cope with physiological challenges. The molecular actions of glucocorticoids are mediated by glucocorticoid receptor-dependent regulation of nearly 25% of the ...[more]

PMID: 24300895

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Project description:Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by neuronal degeneration, telangiectasias, acute cancer predisposition, and hypersensitivity to ionizing radiation (IR). The gene defective in AT, ATM (for AT-mutated), encodes a protein, pATM that has been found to have IR-inducible kinase activity. Cells from individuals with AT exhibit severely attenuated cell cycle checkpoints in response to gamma radiation exposure. pATM has been hypothesized to act as part of a complex that senses DNA damage, in particular, DNA double strand breaks. We are studying the pATM-dependent gene expression responses to a dose of 1.5 Gy radiation in lymphoblastoid cell lines from multiple individuals with either wild type or mutated ATM. The gene expression analyses were performed on Agilent Human 1A Oligo chips containing approximately 16,000 60mer probes. We identified a set of genes whose gene expression changes are ATM-dependent following exposure to 1.5 Gy IR. This set of genes was tested by real time quantitative PCR analysis. The study consists of one dose group - 1.5 Gray gamma radiation. Samples were collected 6 hr following irradiation (treated) or mock irradiation (controls) for each culture. Each culture has a treated sample and a control sample. There are cultures from 6 wild-type ATM individuals and cultures from 6 individuals that are ATM-deficient, for a total of 12 cultures. Hybridizations compared RNA extracted from each individual culture's treated sample against its corresponding control sample, and were performed as dye-flip duplicates (1 replicate in each direction). Hybridizations were performed on the Human 1A Oligo Chips using low input, direct labeling at Paradigm Genetics Laboratory. Microarray scanning was performed with the Agilent G2565AA Scanner. Paradigm Standard Operating Procedures were followed for quality analysis, sample labeling, microarray hybridization and washing, scanning, image analysis and initial data analysis.

Project description:High levels of Hes1 expression are frequently found in BCR-ABL-positive chronic myelogenous leukemia in blast crisis (CML-BC). In mouse bone marrow transplantation (BMT) models, co-expression of BCR-ABL and Hes1 induces CML-BC–like disease; however the underlying mechanism remained elusive. Here, based on gene expression analysis, we show that MMP-9 is upregulated by Hes1 in common myeloid progenitors (CMPs). Analysis of promoter activity demonstrated that Hes1 upregulated MMP-9 by activating NF-kB. Analysis of 20 samples from CML-BC patients showed that MMP-9 was highly expressed in three, with two exhibiting high levels of Hes1 expression. Interestingly, MMP-9 deficiency impaired the cobblestone area-forming ability of CMPs expressing BCR-ABL and Hes1 that were in conjunction with a stromal cell layer. In addition, these CMPs secreted MMP-9, promoting the release of soluble Kit-ligand (sKitL) from stromal cells, thereby enhancing proliferation of the leukemic cells. In accordance, mice transplanted with CMPs expressing BCR-ABL and Hes1 exhibited high levels of sKitL as well as MMP-9 in the serum. Importantly, MMP-9 deficiency impaired the development of CML-BC–like disease induced by BCR-ABL and Hes1 in mouse BMT models. The present results suggest that Hes1 promotes the development of CML-BC, partly through MMP-9 upregulation in leukemic cells. Common myeloid progenitors (CMPs; Lineage negative, c-Kit positive, Sca-1 negative, Fc-gamma-receptor low, CD34 positive fraction) were sorted with a FACSAria cell sorter (Becton Dickinson). Retroviruses were generated by transfecting Plat-E packaging cells with retrovirus vector pMYs-Hes1-IRES-GFP or empty vector (pMYs-IRES-GFP) using FuGENE 6 (Roche Diagnostics). Infection of retrovirus harboring Hes1 (pMYs-Hes1-IRES-GFP) or empty vector (pMYs-IRES-GFP) into progenitors was performed using RetroNectin (Takara Bio). Hes1-transfected CMPs and Mock-transduced CMPs were isolated 36 hours after infection with a FACSAria cell sorter. One sample of Hes1-transfected CMPs and one sample of mock-transduced CMPs were analyzed with GeneChip Mouse Genome 430 2.0 Array.

Dataset Information

Hes1 and Glucocorticoid Signaling in Bone Sarcoma Cells

Publications

HES1 is a master regulator of glucocorticoid receptor-dependent gene expression.

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