E2F Deregulation Compromises ER homeostasis by Attenuating IRE1 Activity
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ABSTRACT:
PROVIDER: PRJNA1249023 | ENA |
REPOSITORIES: ENA
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Project description:The E2F family of transcription factors is an essential regulator of the cell cycle across all metazoan and is often deregulated in cancer. While their primary function is in cell cycle control, E2Fs also influence various cellular processes, such as apoptosis and metabolism. Previous studies in mice have shown that E2F deregulation particularly affect exocrine tissues such as the salivary gland and pancrease. However, the mechanisms behind exocrine cell sensitivity to E2F loss remain inadequately explored. Our lab recently discovered a novel alternatively spliced isoform of Drosophila de2f1, de2f1b, with an additional 16 amino acids than the canonical isoform of de2f1, de2f1a. de2f1b mutants have defects in development of polyploid tissues such as larval salivary glands (SG). Interestingly, SGs of de2f1b mutant shows DNA damage, accumulate cytoplasmic DNA and activation of immune response. This RNA-seq study is to create a gene expression profile of the de2f1b SGs to get a comprehensive understanding of the effects of de2f1b mutation in exocrine tissues.
2025-09-01 | GSE294319 | GEO
Project description:Several studies described a role for the E2F/Rb pathway in ovarian serous carcinomas (SCAs). Since E2F/Rb pathway deregulation is a general hallmark of human cancer, it remains unclear whether this deregulation is of particular importance in SCAs or whether it reflects a common oncologic feature. Here, we attempted to clarify this issue by the examination of microarray expression profiles of SCAs (10 SCA1s, 15 SCA3s) and particularly by the comparison with another, less malignant, ovarian cancer type, serous borderline tumours (13 SBTs). Results were further validated by quantitative RT-PCR, both on the microarray samples and an independent panel. In addition, TP53 mutation analysis was performed. This integrated analysis revealed a significant increase in the expression of the transcription factors E2F1 and E2F3 in SCAs, when compared to SBTs. This was associated with a vast overexpression of E2F target genes in SCAs compared to SBTs. Overall, at least 45% of those genes with a significantly higher expression in SCAs were E2F targets. When taking into account the different SCA tumour grades, particularly SCA3s exhibited a major deregulated E2F target expression pattern, compared to SBTs. To a lesser extent, this was also the case for SCA1s, although the E2F target expression pattern of several SCA1s appeared to be more similar to SBTs. Generally, overexpression of E2F targets in SCAs appeared to be well-structured since those targets considered as negative regulators of the cell cycle or promoters of apoptosis were usually not overexpressed in SCAs. Similar to E2F target deregulation, TP53 mutations were identified in SCA3s, to a lesser extent in SCA1s, and not in SBTs. These results suggest that a structured, generally upregulated, E2F transcription factor activity is associated with a global cell cycle disturbance in high grade SCAs, and exceeds typical E2F/Rb pathway disruption in tumours, at least compared with SBTs
2008-08-21 | GSE12471 | GEO
Project description:Gene transcription is a highly regulated process, and deregulation of transcription factors activity underlie numerous pathologies including cancer. FOXK1 and FOXK2 (FOXK1/2) transcription factors have recently emerged as important regulators of cell metabolism, autophagy and cell differentiation. While FOXK1/2 possesses many overlapping functions in normal biology, their specific functions as well as deregulation of their transcriptional activity in cancer is less clear and often contradictory. FOXK1, but less FOXK2, is known to have oncogenic properties as higher expression levels of FOXK1 has been observed in several cancers and is correlated with tumor progression, invasion, and metastasis. However, the molecular mechanism by which FOXK1 exert its oncogenic properties in caner remains unknown. Here we show that elevated expression of FOXK1, but not FOXK2, in normal human fibroblasts promotes transcription of E2F target genes associated with increased proliferation and delayed senescence entry. Fibroblasts overexpressing FOXK1 are also more prone to cellular transformation with minimal oncogenic combinations, suggesting important oncogenic proprieties of FOXK1. Mechanistically, we found that FOXK1, but not FOXK2, is specifically modified by O-GlcNAcylation. FOXK1 O-GlcNAcylation is modulated during the cell cycle and its highest levels coincides with the G1/S phase transition. Moreover, FOXK1 O-GlcNAcylation is increased following cell transformation and loss of this modification leads to decreased FOXK1 ability to promote cellular transformation and tumor growth. Cells overexpressing FOXK1 O-GlcNAcylation-defective mutants have lower E2F1 expression, cell proliferation, and tumour growth. Our results define a distinct role of FOXK1 via O-GlcNAcylation in controlling the cell cycle through the orchestration of the E2F pathway.
2024-06-10 | PXD050014 | Pride
Project description:We investigate the contribution of IRE1 signaling to the modulation of U87 glioma cells transcriptome upon various stresses. To this end, IRE1 control and IRE1 dominant negative expressing U87 glioma cells were subjected to environmental or chemical challenges and their transcriptome monitored using Affymetrix microarrays. Stress-induced transcriptome modulation in function of IRE1 proficiency/deficiency
2011-12-31 | E-GEOD-27306 | biostudies-arrayexpress
Project description:Activation of the IRE1/XBP1s signaling arm of the unfolded protein response (UPR) is a promising strategy to correct defects in endoplasmic reticulum (ER) proteostasis implicated in diverse diseases. However, no pharmacologic activators of this pathway identified to date are suitable for ER proteostasis remodeling through selective activation of IRE1/XBP1s signaling. Here, we use high-throughput screening to identify non-toxic compounds that induce ER proteostasis remodeling through IRE1/XBP1s activation. We employ transcriptional profiling to stringently confirm that our prioritized compounds selectively activate IRE1/XBP1s signaling without activating other cellular stress-responsive signaling pathways. Furthermore, we demonstrate that our compounds improve ER proteostasis of destabilized variants of amyloid precursor protein (APP) through an IRE1-dependent mechanism and reduce APP-associated mitochondrial toxicity in cellular models. These results establish highly-selective IRE1 activating compounds that can be widely employed to define the functional importance of IRE1/XBP1s activity for ER proteostasis regulation in the context of health and disease.
2020-04-17 | GSE148802 | GEO
Project description:Several studies described a role for the E2F/Rb pathway in ovarian serous carcinomas (SCAs). Since E2F/Rb pathway deregulation is a general hallmark of human cancer, it remains unclear whether this deregulation is of particular importance in SCAs or whether it reflects a common oncologic feature. Here, we attempted to clarify this issue by the examination of microarray expression profiles of SCAs (10 SCA1s, 15 SCA3s) and particularly by the comparison with another, less malignant, ovarian cancer type, serous borderline tumours (13 SBTs). Results were further validated by quantitative RT-PCR, both on the microarray samples and an independent panel. In addition, TP53 mutation analysis was performed. This integrated analysis revealed a significant increase in the expression of the transcription factors E2F1 and E2F3 in SCAs, when compared to SBTs. This was associated with a vast overexpression of E2F target genes in SCAs compared to SBTs. Overall, at least 45% of those genes with a significantly higher expression in SCAs were E2F targets. When taking into account the different SCA tumour grades, particularly SCA3s exhibited a major deregulated E2F target expression pattern, compared to SBTs. To a lesser extent, this was also the case for SCA1s, although the E2F target expression pattern of several SCA1s appeared to be more similar to SBTs. Generally, overexpression of E2F targets in SCAs appeared to be well-structured since those targets considered as negative regulators of the cell cycle or promoters of apoptosis were usually not overexpressed in SCAs. Similar to E2F target deregulation, TP53 mutations were identified in SCA3s, to a lesser extent in SCA1s, and not in SBTs. These results suggest that a structured, generally upregulated, E2F transcription factor activity is associated with a global cell cycle disturbance in high grade SCAs, and exceeds typical E2F/Rb pathway disruption in tumours, at least compared with SBTs Experiment Overall Design: Expression levels of 13 SBTs, including 2 micropapillary SBTs (MPCs), 10 SCAs grade 1 (SCA1s), and 15 SCAs grade 3 (SCA3s) were compared.
2008-10-25 | E-GEOD-12471 | biostudies-arrayexpress
Project description:Transcriptional profilling of 60 day old prostate tissue from Rb1F/F:Trp53F/F:PB-Cre4 or Rb1R654W/F:Trp53F/F:PB-cre4 mice versus wild type prostate tissue. Profiles used to compare deregulation of known E2F target genes in prostate tissue expressing a mutant Rb1 gene to tissue lacking Rb1 expression.
2010-11-27 | GSE25615 | GEO
Project description:We investigate the contribution of IRE1 signaling to the modulation of U87 glioma cells transcriptome upon various stresses. To this end, IRE1 control and IRE1 dominant negative expressing U87 glioma cells were subjected to environmental or chemical challenges and their transcriptome monitored using Affymetrix microarrays.
2011-12-31 | GSE27306 | GEO
Project description:We measured steady-state mRNA levels by microarray hybridization, comparing WT, (delta)ire1, (delta)gcn4, and (delta)gcn2 cells treated with 2 mM DTT for 30 min (by which time the UPR is qualitatively complete) to untreated samples of the same genotype. WT cells were taken as a positive control for UPR induction, and (delta)ire1 cells as a negative control. Fold change in expression of a given gene was computed as the ratio of mRNA level in the treated sample to the level in an untreated sample of the same genotype. Values reported here are the log2 fold change. Keywords = unfolded protein response Keywords = UPR Keywords = ire1 Keywords = gcn4 Keywords = gcn2
2010-06-06 | E-GEOD-1688 | biostudies-arrayexpress