TNF-α inhibits the chemotherapy resistance caused by upregulation of the PERK-ATF4 pathway in colorectal cancer cells
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ABSTRACT:
PROVIDER: PRJNA1183815 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31296402_1.fastq.gz | Fastqsanger.gz | |||
| SRR31296402_2.fastq.gz | Fastqsanger.gz | |||
| SRR31296403_1.fastq.gz | Fastqsanger.gz | |||
| SRR31296403_2.fastq.gz | Fastqsanger.gz | |||
| SRR31296404_1.fastq.gz | Fastqsanger.gz |
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Project description:The unfolded protein response (UPR) is a set of important pathways important for maintaining endoplasmic reticulum homeostasis. Recent evidence suggests that the UPR plays an important role in chemo-resistance. However, the underlying mechanisms are not well understood. We previously found that the PERK pathway, one of three branches of the UPR pathway, is crucial for the resistance of colorectal cancer (CRC) cells to 5-fluorouracil. In this study, we demonstrated that activating transcription factor 4 (ATF4), the key downstream factor of the PERK pathway, is overexpressed in human CRCs and associated with a poor prognosis. Loss of ATF4 sensitized CRC cells to multiple chemotherapy drugs. RNA-seq analysis revealed that the TNF-α signaling pathway was significantly induced upon chemotherapy drug treatment while repressed by ATF4-knockdown. Addition of TNF-α can further potentiate the cytotoxic effects of chemotherapy drugs to ATF4-knockdown cells, highlighting a potential role of the TNF-α signaling pathway in regulating the ATF4-mediated drug sensitivity modulation. In summary, our findings provide a promising approach to overcoming chemotherapy resistance in colon cancer.
2024-11-10 | GSE281408 | GEO
Project description:To identify the target genes of integrated stress reponse (ISR), we have employed whole genome microarray expression in MEF cells. ISR gene setimation under ER stress condition using Perk -/-, Atf4 -/-, eIF2a S51A mutant, Fv2E-PERK MEF cells
2015-09-01 | E-GEOD-49598 | biostudies-arrayexpress
Project description:Here we report that the Th2 cytokine IL-4 and the tumor microenvironment activated protein kinase RNA-like ER kinase (PERK) ER stress signaling cascade to promote immunosuppressive M2 activation and proliferation. Lacking PERK signaling impeded mitochondrial respiration and lipid oxidation critical for M2 macrophages. In addition, PERK activation mediated the upregulation of PSAT1 and serine biosynthesis via the downstream transcription factor ATF4.
2022-01-01 | GSE165836 | GEO
Project description:Here we report that the Th2 cytokine IL-4 and the tumor microenvironment activated protein kinase RNA-like ER kinase (PERK) stress signaling cascade to promote immunosuppressive M2 activation and proliferation. PERK activation mediated the upregulation of PSAT1 and serine biosynthesis via the downstream transcription factor ATF4. We found that Increased serine biosynthesis could result in enhanced mitochondrial function and α-ketoglutarate (α-KG) production required for JMJD3-dependent epigenetic modification.
2022-01-01 | GSE183287 | GEO
Project description:By using small RNA-seq, we report microRNA profilings from Perk knockdown C2C12 cells, differentiated C2C12 cells, Atf4 overexpressed C2C12 cells, Perk knockdown P19 cells and negative control.
2021-03-01 | GSE167878 | GEO
Project description:Disruptions of protein homeostasis in the endoplasmic reticulum (ER) elicit activation of the unfolded protein response (UPR), a translation- and transcription-coupled proteostatic stress response pathway. The primary translational control arm of the UPR is initiated by the PERK-dependent phosphorylation of eIF2α, leading to a large-scale reprogramming of translation and subsequent activation of an ATF4-mediated transcriptional program. It has remained challenging, however, to accurately evaluate the contribution of each component of the eIF2α/ATF4 pathway to the remodelling of transcription and translation. Here, we have used mouse embryonic fibroblasts containing either a knock-in of the non-phosphorylatable eIF2α S51A mutant or knock-out for ATF4 by ribosome profiling and mRNA-seq to define the specific contributions of eIF2α phosphoryation and ATF4 in controlling the translational and transcriptional components of the UPR. These studies show that the transcriptional and translational targets of each P-eIF2α, ATF4, and the other UPR gene expression programs overlapped extensively, leading to a core set of UPR genes whose robust expression in response to ER stress is driven by multiple mechanisms. The identification of other, more factor-specific targets illustrated the potential for functional specialization of the UPR. As the UPR progressed temporally, cells employed distinct combinations of transcriptional and translational mechanisms, initiated by different factors, to adapt to ongoing stress. These effects were accompanied by a buffering effect where changes in mRNA levels were coupled to opposing changes in ribosome loading, a property which makes cooperation between transcription and translation essential to confer robust protein expression. Translational analysis by ribosome profiling and mRNA-seq of PERK pathways mutants during the UPR. Mouse embryonic fibroblasts (MEFs) lacking components of the PERK pathway (eIF2a phosphorylation and ATF4) were subjected to ER stress and analyzed by ribosome profiling.
2016-07-03 | E-GEOD-68265 | biostudies-arrayexpress
Project description:It is now well-accepted that cancers co-opt the microenvironment to support their growth. However, the molecular mechanisms underlying cancer-microenvironment interactions remain poorly defined. We have found that Rho-associated kinase (ROCK) activity in the epithelial component of mammary tumors selectively actuates Protein kinase R-like endoplasmic reticulum kinase (Perk), causing the recruitment and persistent education of tumor-promoting cancer-associated fibroblasts (CAFs), a key component of the cancer microenvironment. Analysis of tumors from mice and human patients identified Cysteine-rich with EGF-like domains 2 (CRELD2), as the paracrine factor underlying PERK-mediated CAF-education downstream of ROCK. CRELD2 expression was found to be regulated by ATF4 downstream of the PERK pathway and knock-down of CRELD2 prevented tumor progression, demonstrating that the paracrine ROCK-PERK-ATF4-CRELD2 axis is a promoter of breast cancer progression and suggesting new therapeutic opportunities.
2020-05-27 | PXD018253 | Pride
Project description:Disruptions of the endoplasmic reticulum (ER) that perturb protein folding cause ER stress and elicit an unfolded protein response (UPR) that involves translational and transcriptional changes in gene expression aimed at expanding the ER processing capacity and alleviating cellular injury. Three ER stress sensors PERK, ATF6, and IRE1 implement the UPR. PERK phosphorylation of eIF2 during ER stress represses protein synthesis, which prevents further influx of ER client proteins, along with preferential translation of ATF4, a transcription activator of the integrated stress response. In this study we show that the PERK/eIF2α~P/ATF4 pathway is required not only for translational control, but also activation of ATF6 and its target genes. The PERK pathway facilitates both the synthesis of ATF6 and trafficking of ATF6 from the ER to the Golgi for intramembrane proteolysis and activation of ATF6. As a consequence, liver-specific depletion of PERK significantly reduces both the translational and transcriptional phases of the UPR, leading to reduced protein chaperone expression, disruptions of lipid metabolism, and enhanced apoptosis. These findings show that the regulatory networks of the UPR are fully integrated, and helps explain the diverse pathologies associated with loss of PERK. 14 gene expression arrays, 3 WT control arrays; 3 lsPERK control arrays; 4 WT Treated arrays; 4 lsPERK treated arrays. Comparison of gene expression profiles for treated vs control in wildtype and knock-out.
2012-01-20 | E-GEOD-29929 | biostudies-arrayexpress
Project description:UTX/KDM6A encodes a major histone H3 lysine 27 (H3K27) demethylase which is frequently mutated in various types of cancers. Although UTX appears to play a crucial role in cancer, its mechanisms remain poorly understood. Here we found that a specific pharmacological inhibitor of H3K27 demethylases, GSK-J4, induces expression of the ATF4 (transcription activating factor 4) protein and its downstream target genes (e.g. PCK2, CHOP, REDD1, CHAC1 and TRIB3), and activates autophagy-related gene products (LC3A, LC3B and ATG5-ATG12). ATF4 induction by GSK-J4 did not entail either ATF6α processing or an increase of PERK and eIF2α serine 51 phosphorylation, indicating that this action is not triggered by canonical endoplasmic reticulum (ER) stress. No changes in expression levels of the endogenous ATF4 mRNA and exogenously expressed ATF4 proteins driven by the CMV promoter were detected, suggesting that the induction is not due to either transcriptional or post-translational regulation of ATF4. Although GSK-J4 efficiently induces apoptosis, it is unlikely that the induction is due to activation of the ATF4-CHOP axis. By using gene expression profiling experiments in conjunction with CRISPR editing and stable re-expression of UTX, we found that UTX specifically suppresses expression of ATF4 target genes. These findings highlight not only that GSK-J4, which has been considered an anti-cancer drug, is a strong inducer of ATF4, but also that UTX is an important component of this regulation and may contribute to oncogenesis via ATF4 regulation.
2019-12-31 | GSE127860 | GEO
Project description:Disruptions of the endoplasmic reticulum (ER) that perturb protein folding cause ER stress and elicit an unfolded protein response (UPR) that involves translational and transcriptional changes in gene expression aimed at expanding the ER processing capacity and alleviating cellular injury. Three ER stress sensors PERK, ATF6, and IRE1 implement the UPR. PERK phosphorylation of eIF2 during ER stress represses protein synthesis, which prevents further influx of ER client proteins, along with preferential translation of ATF4, a transcription activator of the integrated stress response. In this study we show that the PERK/eIF2α~P/ATF4 pathway is required not only for translational control, but also activation of ATF6 and its target genes. The PERK pathway facilitates both the synthesis of ATF6 and trafficking of ATF6 from the ER to the Golgi for intramembrane proteolysis and activation of ATF6. As a consequence, liver-specific depletion of PERK significantly reduces both the translational and transcriptional phases of the UPR, leading to reduced protein chaperone expression, disruptions of lipid metabolism, and enhanced apoptosis. These findings show that the regulatory networks of the UPR are fully integrated, and helps explain the diverse pathologies associated with loss of PERK.
2012-01-20 | GSE29929 | GEO