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Genome-wide analysis of insulin-like growth factor 1 receptor (IGF1R) binding sites in DFB cells

ABSTRACT: The insulin-like growth factor 1 receptor (IGF-1R) plays crucial roles in developmental and cancer biology. Most of its biological effects have been ascribed to its tyrosine kinase activity. We report that IGF-1 promotes the modification of IGF-1R by small ubiquitin-like modifier protein-1 (SUMO-1) and its translocation to the nucleus. Nuclear IGF-1R associated with enhancer-like elements and increased transcription in reporter assays. We used ChIP-seq to examine the interaction of IGF-1R with DNA on a genome-wide scale. Analysis of the data set resulted in 568 candidate peaks, that is, statistically significant IGF-1R-enriched regions. The IGF-1R-enriched regions were divided into five classes on the basis of their location relative to known genes. Most of the IGF-1R-interacting sites (80%) were located distal from any annotated gene (intergenic), 6.3% were located in introns, 6.3% in exons, 3.4% were <20 kb upstream of an annotated transcript start site (5'UTR + 20 kb upstream), and 3.6% were <20 kb downstream of an annotated transcript end site (3'UTR + 20 kb downstream).

ORGANISM(S): Homo sapiens

PROVIDER: GSE23792 | GEO | 2010/08/25

SECONDARY ACCESSION(S): PRJNA130715

REPOSITORIES: GEO

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Genome-wide analysis of insulin-like growth factor 1 receptor (IGF1R) binding sites in DFB cells

Project description:The insulin-like growth factor 1 receptor (IGF-1R) plays crucial roles in developmental and cancer biology. Most of its biological effects have been ascribed to its tyrosine kinase activity. We report that IGF-1 promotes the modification of IGF-1R by small ubiquitin-like modifier protein-1 (SUMO-1) and its translocation to the nucleus. Nuclear IGF-1R associated with enhancer-like elements and increased transcription in reporter assays. We used ChIP-seq to examine the interaction of IGF-1R with DNA on a genome-wide scale. Analysis of the data set resulted in 568 candidate peaks, that is, statistically significant IGF-1R-enriched regions. The IGF-1R-enriched regions were divided into five classes on the basis of their location relative to known genes. Most of the IGF-1R-interacting sites (80%) were located distal from any annotated gene (intergenic), 6.3% were located in introns, 6.3% in exons, 3.4% were <20 kb upstream of an annotated transcript start site (5'UTR + 20 kb upstream), and 3.6% were <20 kb downstream of an annotated transcript end site (3'UTR + 20 kb downstream). Analysis of the genomic interaction of IGF1R in DFB cells

2010-08-25 | E-GEOD-23792 | biostudies-arrayexpress

Knockdown IGF-1R triggers viral RNA sensors MDA5- and RIG-1-mediated the mitochondrial apoptosis in colonic cancer cells

Project description:The important role of IGF-1R in cancers has been well established. Classical model involves IGF-1/2 binding to IGF-1R, following activation of the PI3K/Akt pathway, thereby promoting cell proliferation, apoptosis inhibition and treatment resistance. While IGF-1R has become a promising target for cancer therapy, clinical disclosures subsequently have been less encouraging. The question is whether targeting IGF/IGF-1R still holds therapeutic potential. Here we show a novel mechanism that knockdown IGF-1R surprisingly triggers cytoplasmic viral RNA sensors MDA5 and RIG-1, leading to mitochondrial apoptosis in cancer. We analyzed MDA5 and RIG-1 in the intestinal epithelium of IGF-1R knockdown mice. Igf1r+/- mice demonstrated higher MDA5 and RIG-1 than WT mice. IGF-1R knockdown-triggered MDA5 and RIG-1 was further analyzed in human cancer and normal cells. Increased MDA5 and RIG-1 were clearly seen in the cytoplasm identified by immunofluoresce in the cells silenced IGF-1R. Block off IGF-1R downstream PI3K/Akt did not impact on MDA5 and RIG-1 expression. IGF-1R knockdown-triggered MDA5 and RIG-1 and their signaling pathways were similar to those of viral RNA mimetic poly(I:C) had. IGF-1R knockdown-triggered MDA5 and RIG-1 led to cancer apoptosis through activation of the mitochondrial pathway. In vivo assay, Igf1r+/- mice strongly resisted AOM-induced colonic tumorigenesis through triggering MDA¬5- and RIG-1-mediated apoptosis. Notably, RIG-I and MDA5-mediated proapoptotic signaling pathway is preferential active in cancer cells. These data suggest that targeting IGF-1R-triggered MDA5 and RIG-1 might have therapeutic potential for cancer treatment.

2019-11-30 | GSE122534 | GEO

Identification of pro-metastatic pathways and molecules in mouse models with reduced expression or signaling of the insulin-like growth factor type 1 receptor

Project description:We performed single-cell RNA sequencing of multiple IGF-1R loss-of function mouse mammary tumor models to uncover how IGF-1R signaling regulates intrinsic epithelial cell signaling to suppress metastasis. We identify key pathways necessary for promoting metastasis, determined IGF-1R is required to maintain a metastatic suppressive tumor microenvironment and demonstrate that attenuated epithelial IGF-1R signaling in the MMTV-Wnt1 mouse tumor model is sufficient for metastatic invasion. We further show that adherence between luminal and basal tumor cells is necessary for tumor growth at the secondary site and that reduced IGF-1R signaling in tumor epithelial cells inhibits secondary tumor epithelial cell growth due to dysregulated E-cadherin and P-cadherin and loss of cell-cell adhesion.

2022-11-21 | GSE182236 | GEO

Gene expression profiling of IR-/-, IGF-1R-/- (dKO) newborn epidermis.

2013-05-18 | GSE47065 | GEO

Homo sapiens

Project description:Nucleosome mapping in 20 kb upstream regions of microRNAs

| PRJNA102529 | ENA

Microenvironment-driven IGF-1R/PI3K signaling underlies acquired resistance to CSF1R inhibition in gliomas (CGH)

Project description:Macrophages accumulate with glioblastoma multiforme (GBM) progression, and can be acutely targeted via inhibition of colony stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. Here, we investigate whether long-term CSF-1R inhibition can stably regress GBM in preclinical trials. We show that while overall survival is significantly prolonged, tumors recur eventually in >50% of mice. Upon isolation and transplantation of recurrent tumor cells into naïve animals, gliomas re-establish sensitivity to CSF-1R inhibition, indicating that resistance is microenvironment-driven. PI3K pathway activity was elevated in recurrent GBM, driven by macrophage-derived IGF-1 and tumor cell IGF-1R. Consequently, combining IGF-1R or PI3K blockade with continuous CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. By contrast, monotherapy with IGF-1R or PI3K inhibitors in rebound or treatment-naïve tumors was less effective, indicating the necessity of combination therapy to expose PI3K signaling-dependency in recurrent disease. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors in the clinical setting.

2016-05-20 | GSE80399 | GEO

Identification of phosphorylation sites in the IGF-1 Receptor

Project description:Although Insulin-like Growth Factor (IGF-1) signaling promotes tumor growth and cancer progression, IGF-1 Receptor-targeted therapies have shown poor clinical efficacy. The mechanistic basis for this is unclear as is our understanding of what distinguishes IGF-1R signaling from the closely related Insulin receptor (IR) signaling. This study illuminates both issues. A site in the IGF-1R C-terminal tail incorporating two tyrosines that are not present in the Insulin receptor (IR) was previously shown to be essential for IGF-1-mediated cancer cell survival, migration and tumorigenic growth. Here, we establish that the Y1250/Y1251 site is autophosphorylated in a cell adhesion-dependent manner.

2020-05-15 | PXD017644 | Pride

Gene expression profiling of IR-/-, IGF-1R-/- (dKO) newborn epidermis.

Project description:Analysis of newborn mouse epidermis lacking the expression of Insulin receptor (IR) and Insulin like growth factor 1 receptor (IGF-1R). Results show that IR/IGF-1R signalling control epidermal morphogenesis. RNA was isolated from newborn mouse epidermis.Gene expression profiling was on on Affymetrix 430-2.0 platform.

2013-05-18 | E-GEOD-47065 | biostudies-arrayexpress

Expression data from IGF-1R targeting in 33 NCI-H526 SCLC (small-cell lung cancer) xenografts

Project description:Insulin-like growth factor receptor-1 (IGF-1R) inhibition could be a relevant therapeutic approach in small cell lung cancer (SCLC) given the importance of an IGF-1R autocrine loop and its role in DNA damage repair processes. We assessed IGF-1R and pAkt protein expression in 83 SCLC human specimens. The efficacy of R1507 (a monoclonal antibody directed against IGF-1R) alone or combined with cisplatin or ionizing radiation (IR) was evaluated in H69, H146 and H526 cells in vitro and in vivo. Innovative genomic and functional approaches were conducted to analyze the molecular behavior under the different treatment conditions. A total of 53% and 37% of human specimens expressed IGF-1R and pAkt, respectively. R1507 demonstrated single agent activity in H146 and H526 cells but not in H69 cells. R1507 exhibited synergistic effects with both Cisplatin and IR in vitro. The triple combination R1507-Cisplatin-IR led to a dramatic delay in tumor growth compared to Cisplatin-IR in H526 cells. Analyzing the apparent absence of antitumoral effect of R1507 alone in vivo, we observed a transient reduction of IGF-1R staining intensity in vivo, concomitant to the activation of multiple cell surface receptors and intracellular proteins involved in proliferation, angiogenesis and survival. Finally, we identified that the nucleotide excision repair pathway (NER) was mediated after exposure to R1507-CDDP and R1507-IR in vitro and in vivo. In conclusion, adding R1507 to the current standard Cisplatin-IR doublet reveals remarkable chemo- and radiosensitizing effects in selected SCLC models and warrants to be investigated in the clinical setting. We used microarrays to investigate the effect of IGF-1R targetting on the global gene expression.

2013-03-30 | GSE45626 | GEO

In vitro proteomic expression changes in Ewing sarcoma cell lines after IGF-1R or IGF-1R/IR blockade

Project description:Ewing Sarcoma is caused by a pathognomonic genomic translocation that places an N-terminal EWSR1 gene in approximation with one of several ETS genes (typically FLI1). This aberration, in turn, alters the transcriptional regulation of more than five hundred genes and perturbs a number of critical pathways that promote oncogenesis, cell growth, invasion, and metastasis. Among them, translocation-mediated up-regulation of the insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) are of particular importance since they work in concert to facilitate IGF-1R expression and ligand-induced activation, respectively, of proven importance in ES transformation. When used as a single agent in Ewing sarcoma therapy, IGF-1R or mTOR inhibition leads to rapid counter-regulatory effects that blunt the intended therapeutic purpose. Therefore, identify new mechanisms of resistance that are used by Ewing sarcoma to evade cell death to single-agent IGF-1R inhibition might suggest a number of therapeutic combinations that could improve its clinical activity.

2016-06-01 | GSE78121 | GEO

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