Glucocorticoids delay RAF-induced senescence promoted by EGR1
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ABSTRACT:
PROVIDER: PRJNA556258 | ENA |
REPOSITORIES: ENA
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Project description:Glucocorticoids delay RAF-induced senescence promoted by EGR1 [ChIP-seq]
| PRJNA556815 | ENA
Project description:Analysis of the transcriptional response to treatment with glucocorticoids in human fibroblasts entering oncogene-induced senescence.
2019-08-27 | GSE134747 | GEO
Project description:Analysis of the differential binding of EGR1 to chromatin in human fibroblasts entering oncogene-induced senescence, with and without clobetasol.
2019-08-27 | GSE134924 | GEO
Project description:In this study we used CRISPR/Cas9 to generate KO clones of the HEK-RAF-ER cell line that lack expression of EGR1, FOS and profiled the transcriptome after inducing RAF/MAPK signaling.
2024-01-13 | GSE250532 | GEO
Project description:Human bone marrow stromal cells (BMSCs) are key elements of the hematopoietic environment and they play a central role in bone and bone marrow physiology. However, how key BMSC functions are regulated is largely unknown. We analyzed the role of the immediate early response transcription factor EGR1 as key BMSC regulator and found that EGR1 was highly expressed in prospectively-isolated primary BMSCs, downregulated upon culture, and lower in non-CFU-F-containing CD45neg BM cells. Furthermore, EGR1 expression was lower in proliferative regenerating adult and fetal primary cells compared to adult steady-state BMSCs. Accordingly, EGR1 overexpression markedly decreased BMSC proliferation but considerably improved hematopoietic stroma support function as indicated by an increased production of transplantable CD34+CD90+ hematopoietic stem cells in expansion co-cultures. The improvement of BMSC stroma support function was mediated by increased expression of hematopoietic supporting genes, such as VCAM1 and CCL28. On the other hand, EGR1 knockdown increased ROS-mediated BMSC proliferation, and clearly reduced BMSC hematopoietic stroma support potential. These findings thus show that EGR1 is a key BMSC transcription factor with a dual role in regulating proliferation and hematopoietic stroma support function that is controlling a genetic program to coordinate the specific functions of BMSC in their different biological contexts.
2019-06-27 | PXD011767 | Pride
Project description:Previous studies have revealed that UV-stimulation of a variety of cells leads to activation of the EGF receptor, induction of Egr1, growth inhibition and apoptosis. On the other hand both Egr1 and EGF receptor activation are implicated in promoting the progression of prostate cancer. We treated M12 tumorigenic prostate epithelial cells which express little Egr1 with UV irradiation which rapidly activated the EGF receptor and elevated Egr1. Treatment with specific EGFR and ERKI/II inhibitors (PD153035 and UO126, respectively) confirmed that the upregulation of Egr1 was downstream of EGFR and ERKI/II Map kinase pathway. ChIP on chip experiments using Egr1 antibody identified 288 significantly bound promoters upon UV stimulation. Of these target genes, 40% had consensus Egr1 site in their promoters, considerably greater than that expected by chance (p < 0.005). The array binding results were validated by PCR analysis of 25 genes using DNA from conventional IP experiment. Affymetrix gene expression analysis of UV treated and control cells confirmed that a significant number of these bound promoters showed gene expression changes. Addition of siRNA to Egr1 confirmed that the gene expression changes were dependent upon Egr1 expression. Addition of EGF led to similar expression changes for nine tested genes. Proliferation and apoptosis assays confirmed that M12 cells undergo growth arrest and apoptosis following UV irradiation. Moreover, addition of EGF also promoted significant growth inhibition. These results indicate the M12 cells undergo a EGF receptor dependent apoptosis response upon UV-stimulation and that Egr1 mediates the regulation of numerous genes downstream of the EGF receptor that are associated with this response. Keywords: UV treatment analysis duplicated experiment for Affymetrix gene expression analysis and Chip-on-Chip analysis.
2010-05-06 | E-GEOD-10585 | biostudies-arrayexpress
Project description:Mutations in oncogenes such as KRAS, NRAS and BRAF promote cancer cell survival and proliferation, while excessive RAS/RAF/MEK/ERK signaling instead exerts an inhibitory effect on tumor growth. The precise regulatory mechanism of moderate RAS/RAF/MEK/ERK pathway activation during tumorigenesis remains elusive. Here, we discovered that a circular RNA, circRAPGEF5, was significantly upregulated in KRAS mutant colorectal cancer (CRC) cells. CircRAPGEF5 suppressed mutant and constitutively activated KRAS and the expression of the death receptor TNFRSF10A. Silencing of circRAPGEF5 induced RAS/RAF/MEK/ERK signaling hyperactivation and apoptosis in CRC cells. Moreover, the circularization of circRAPGEF5 was promoted by EIF4A3, whose expression was also elevated in tumor tissues. Taken together, our findings reveal a mechanism of accurate regulation of RAS/RAF/MEK/ERK signaling during CRC progression and provide potential targets for cancer therapy.
2026-06-13 | GSE269456 | GEO
Project description:The clinical benefit benefit of small-molecule inhibitors targeting the MAPK pathway depends on achieving greater pathway inhibition in tumors than in normal tissues, thereby maintaining a high therapeutic index (TI). Selective BRAF inhibitors (BRAFis), developed to inhibit BRAF monomer–mediated signaling downstream of RAS, have shown activity in BRAF-mutant tumors, and combinations with MEK inhibitors (MEKis) administered at their maximum tolerated doses (MTD) have been clinically successful. Next-generation pan-RAF inhibitors (pan-RAFis), developed to inhibit RAF dimer–mediated signaling downstream of RAS, have shown activity in RAS-mutant (RAS-MUT) tumors as single agents. However, combining pan-RAFis with MEKis requires dose reductions due to toxicity, resulting in limited clinical benefit. We find that this toxicity stems from MEK inhibition relieving feedback, which enhances RAF activation and pan-RAFi binding in normal cells, driving excessive MAPK suppression and narrowing the TI. Across preclinical studies and clinical trials, such regimens have reached a “therapeutic ceiling” defined by predominant stable disease and only rare regressions. RAF/MEK glues represent a new class of MEK inhibitors that stabilize RAF–MEK complexes and suppress RAF activity. While structural studies have shown these glues bound to both active and inactive RAF conformations, we demonstrate that their inactivating function arises from a biochemical mechanism of spatial trapping: MEK is constitutively cytosolic, and RAF/MEK glues retain RAF in the cytosol, preventing its membrane recruitment and dimerization required for activation. Consistent with this model, in RAS(MUT) models from various tumor types, the RAF/MEK glue avutometinib, when combined with a pan-RAFi, was tolerated at full dose and, importantly, induced tumor regressions, including achieving a 90% overall response rate (ORR) compared to 0% with a conventional pan-RAFi + MEKi regimen in an insensitive KRAS(MUT) model. Tumor regression correlated with deeper MAPK suppression by pharmacodynamic and transcriptional readouts, without evidence of added toxicity. These findings uncover a previously unrecognized mechanism of RAF inactivation by RAF/MEK glues and demonstrate that replacing the MEKi with a RAF/MEK glue can overcome the “therapeutic ceiling” of current MAPK-targeting therapies, shifting outcomes from predominantly stable disease to frequent tumor regressions. More broadly, this work introduces drug-induced proximity as a strategy to reprogram the spatial and biochemical state of wild-type effectors, thereby expanding the therapeutic window for oncogenic pathway-directed therapies and providing a paradigm shift in precision oncology.
2026-08-17 | GSE343545 | GEO
Project description:To gain insight into the function of DNA-PKcs within immune cells, we performed a quantitative phosphoproteomic screen in T cells to identify first order phosphorylation targets of DNA-PKcs. Results indicate that DNA-PKcs phosphorylates the transcription factor Egr1 (early growth response protein 1) at S301. Expression of Egr1 is induced early upon T cell activation and dictates T cell response by modulating expression of cytokines and key costimulatory molecules. Mutation of serine 301 to alanine via CRISPR-Cas9 resulted in increased proteasomal degradation of Egr1 and a decrease in Egr1-dependent transcription of IL2 (interleukin-2) in activated T cells. Our findings identify DNA-PKcs as a critical intermediary link between T cell activation and T cell fate and a novel phosphosite involved in regulating Egr1 activity.
2021-12-21 | PXD026352 | Pride
Project description:EGR1-mediated ibrutinib resistance
| PRJNA925145 | ENA