Apurinic/apyrimidinic endonuclease/redox factor-1 (Ape1/Ref-1) activates Notch signaling through Jagged1 expression and promotes colon cancer progression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Ho Jin You
PROVIDER: E-GEOD-45912 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:To investigate the possible role of Ape1/Ref-1 in tumorigenicity of colon cancer and explored the oncogenic mechanism of Ape1/Ref-1 in colon cancer cells.
2013-04-17 | GSE45912 | GEO
Project description:The presence of oxidized DNA lesions, such as 7,8-dihydro-8-oxoguanine (8-oxoG) and apurinic/apyrimidinic sites (AP sites), has been described as epigenetic signals that are involved in gene expression control. In mammals, Apurinic-apyrimidinic endonuclease 1/Redox factor-1 (APE1/Ref-1) is the main AP endonuclease of the base excision repair (BER) pathway and is involved in active demethylation processes. In addition, APE1/Ref-1, through its redox function, regulates several transcriptional factors. However, the transcriptional control targets of each APE1 function are not completely known. In this study, a transcriptomic approach was used to investigate the effects of chemical inhibition of APE1/Ref-1 redox or DNA repair functions by E3330 or methoxyamine (MX) in an inflammatory cellular model. Under lipopolysaccharide (LPS) stimulation, both E3330 and MX reduced the expression of some cytokines and chemokines. Interestingly, E3330 treatment reduced cell viability after 48 h of the treatment. Genes related to inflammatory response and mitochondrial processes were downregulated in both treatments. In the E3330 treatment, RNA processing and ribosome biogenesis genes were downregulated, while they were upregulated in the MX treatment. Furthermore, in the E3330 treatment, the cellular stress response was the main upregulated process, while the cellular macromolecule metabolic process was observed in MX-upregulated genes. Nuclear respiratory factor 1 (NRF1) was predicted to be a master regulator of the downregulated genes in both treatments, while the ETS transcription factor ELK1 (ELK1) was predicted to be a master regulator only for E3330 treatment. Decreased expression of ELK1 and its target genes and a reduced 28S/18S ratio were observed, suggesting impaired rRNA processing. In addition, both redox and repair functions can affect the expression of NRF1 and GABPA target genes. The master regulators predicted for upregulated genes were YY1 and FLI1 for the E3330 and MX treatments, respectively. In summary, the chemical inhibition of APE1/Ref-1 affects gene expression regulated mainly by transcriptional factors of the ETS family, showing partial overlap of APE1 redox and DNA repair functions, suggesting that these activities are not entirely independent. This work provides a new perspective on the interaction between APE1 redox and DNA repair activity in inflammatory response modulation and transcription.
2021-08-29 | GSE182813 | GEO
Project description:In this study, we demonstrate that SH-42 and SH-80, novel heat shock protein 90 inhibitors, suppress retinal neovascularization via inhibition of hypoxia-mediated angiogenesis. To figure out any genotoxic effect of these compounds related with heat shock protein 90 inhibition, we performed microarray analyses with retinal tissues treated with SH-42 and SH-80 for 7 days. We intravitreally injected PBS, SH42, or SH80 into the right eyes of C57BL/6 male mice (n = 12 per group). PBS-treated mice were regarded as negative control. Four retinal tissues were pooled into 1 test tube and prepared for further analyses.
2013-04-16 | E-GEOD-46057 | biostudies-arrayexpress
Project description:Pancreatic cancer is a complex disease with a desmoplastic stroma, extreme hypoxia, and inherent resistance to therapy. Understanding the signaling and adaptive response of such an aggressive cancer is key to making advances in therapeutic efficacy and understanding disease progression. Redox factor-1 (Ref-1), a redox signaling protein, regulates the DNA binding activity of several transcription factors, including HIF-1. The conversion of HIF-1 from an oxidized to reduced state leads to enhancement of its DNA binding. In our previously published work, knockdown of Ref-1 under normoxia resulted in altered gene expression patterns on pathways including EIF2, protein kinase A, and mTOR. In this study, single cell RNA sequencing (scRNA-seq) and proteomics were used to explore the effects of Ref-1 on metabolic pathways under hypoxia.Results: We also integrated the scRNA data analysis with the proteomic analysis and found that the differentially expressed genes and pathways identified from the scRNA-seq data are highly consistent to the significant proteins observed in the proteomics data, especially for the upregulated cell cycle and transcription pathways and downregulated metabolic, apoptosis and signaling pathways under hypoxia. Conclusion: The scRNA-seq and proteomics data consistently demonstrated down-regulated central metabolism pathways in APE1/Ref-1 knockdown vs scrambled control under both normoxia and hypoxia conditions. Experimental Methods: scRNA-seq comparing pancreatic cancer cells expressing less than 20% of the Ref-1 protein was analyzed using left truncated mixture Gaussian model. Matched samples were also collected for bulk proteomic analysis of the four conditions. scRNA-seq data was validated using proteomics and qRT-PCR. Ref-1’s role in mitochondrial function was confirmed using mitochondrial function assays and qRT-PCR. Results: We also integrated the scRNA data analysis with the proteomic analysis and found that the differentially expressed genes and pathways identified from the scRNA-seq data are highly consistent to the significant proteins observed in the proteomics data, especially for the upregulated cell cycle and transcription pathways and downregulated metabolic, apoptosis and signaling pathways under hypoxia. Conclusion: The scRNA-seq and proteomics data consistently demonstrated down-regulated central metabolism pathways in APE1/Ref-1 knockdown vs scrambled control under both normoxia and hypoxia conditions.
2021-09-09 | PXD020515 | Pride
Project description:In this study, we investigated the safety of locally delivered titanium dioxide nanoaprticles at the level of gene expression in the retina. To figure out any definite dose-dependent effect, we injected titanium dioxide nanoparticles into the vitreous cavity of 8-week-old male C57BL/6 mice at the concentration of presumptive therapeutic concentration (PTC; 130.47 ng/ml) and 10 times PTC (1.30 μg/ml). We intravitreally injected PBS or titanium dioxide nanoparticles into the right eyes of 8-week-old male C57BL/6 mice (n = 12 per group). PBS-treated mice were regarded as negative control. Four retinal tissues were pooled into 1 test tube and prepared for further analyses.
2013-07-20 | E-GEOD-49048 | biostudies-arrayexpress
Project description:In this study, we investigated the gene expression induced by locally delivered gold and silicate nanoaprticles with the diameter of 20 and 100 nm in the retina. We injected nanoparticles into the vitreous cavity of 5-week-old male C57BL/6 mice. Au20 indicates gold nanoparticles of which diameters were 20 nm, Au100 gold nanoparticles of which diameters were 100 nm, Si20 silicate nanoparticles of which diameters were 20 nm, and Si100 silicate nanoparticles of which diameters were 100 nm. We intravitreally injected PBS or nanoparticles (gold and silicate) into the right eyes of 5-week-old male C57BL/6 mice (n = 12 per group). PBS-treated mice were regarded as negative control. Four retinal tissues were pooled into 1 test tube and prepared for further analyses.
2013-07-31 | E-GEOD-49371 | biostudies-arrayexpress
Project description:Gene expression profiles of ZHBTc4 ES cells expressing EGFP, Oct4-EGFP, Nr5a2-EGFP under CAG promoter. Monoclonal cell lines selected by Puromycin were used for analysis. Each of the cell lines was cultured in doxycycline containing media for endogenous Oct4 knock-down. Pupose of this experiment is to investigate the possibility that forced expression of Nr5a2 can replace Oct4 function in the self-renewal of ES cells. Monoclonal ZHBTc4 ES cells expressing EGFP vs Nr5a2-EGFP, Oct4-EGFP vs Nr5a2-EGFP, no replication
2013-11-05 | E-GEOD-52034 | biostudies-arrayexpress
Project description:We used RNA seq tool to identfiy key signaling pathways affected by APE1/Ref-1 in HRECs, which was contrasted to RNA seq data of tumor cell lines.
2023-02-08 | GSE217746 | GEO
Project description:Transcriptional profiling of mouse bone marrow derived macrophages comparing wildtype with CDK5R1 knockout. CDK5R1 is an activating parter for CDK5 and synthesized upon TLRs stimaultion. Activated CDK5 has various target substrates, and functions as a key singnaling regulator in macrophages. Two condition experiments: basal state and LPS-stimulated macrophages for 6 hours. Two biological replicates.
2014-11-20 | E-GEOD-63443 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized by late diagnosis and treatment resistance. Recurrent genetic alterations in defined genes in association with perturbations of developmental cell signaling pathways have been associated with PDAC development and progression. Here, we show that GATA6 contributes to pancreatic carcinogenesis during the temporal progression of pancreatic intraepithelial neoplasia by virtue of Wnt pathway activation. GATA6 is recurrently amplified by both quantitative-PCR and fluorescent in-situ hybridization in human pancreatic intraepithelial neoplasia and in PDAC tissues, and GATA6 copy number is significantly correlated with overall patient survival. Forced overexpression of GATA6 in cancer cell lines enhanced cell proliferation and colony formation in soft agar in vitro and growth in vivo, as well as increased Wnt signaling. By contrast siRNA mediated knockdown of GATA6 led to corresponding decreases in these same parameters. The effects of GATA6 were found to be due to its ability to bind DNA, as forced overexpression of a DNA-binding mutant of GATA6 had no effects on cell growth in vitro or in vivo, nor did they affect Wnt signaling levels in these same cells. A microarray analysis revealed the Wnt antagonist Dickopf-1 (DKK1) as a dysregulated gene in association with GATA6 knockdown, and direct binding of GATA6 to the DKK1 promoter was confirmed by chromatin immunoprecipitation and electrophoretic mobility shift assays. Transient transfection of GATA6, but not mutant GATA6, into cancer cell lines led to decreased DKK1 mRNA expression and secretion of DKK1 protein into culture media. Forced overexpression of DKK1 antagonized the effects of GATA6 on Wnt signaling in pancreatic cancer cells. These findings illustrate that one mechanism by which GATA6 promotes pancreatic intraepithelial neoplasia is by virtue of its activation of canonical Wnt signaling via regulation of DKK1. AsPC1 and A13A cells were stably transfected with a lentivirus expressing mock shRNA or shRNA to GATA6. Each control/shRNA pair (total 4 samples) was analyzed by two-color microarray and the genes commonly dysregulated in both cell lines identified.
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