Prolonged bihemispheric alterations in unfolded protein response related gene expression after experimental stroke

2006 ◽  
Vol 1087 (1) ◽  
pp. 60-66 ◽  
Author(s):  
Anna Rissanen ◽  
Juhani Sivenius ◽  
Jukka Jolkkonen
Keyword(s):  
Gene Expression ◽  
Unfolded Protein Response ◽  
Experimental Stroke ◽  
Related Gene ◽  
Unfolded Protein ◽  
Protein Response

Development and validation of an unfolded protein response-related gene signature to predict overall survival in HNSCC.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18033-e18033
Author(s):  
Jun Chen ◽  
Bei Zhang
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Unfolded Protein Response ◽  
Cox Regression ◽  
Risk Group ◽  
Gene Signature ◽  
Related Gene ◽  
Hallmarks Of Cancer ◽  
Unfolded Protein ◽  
Protein Response

e18033 Background: Genomic expression profiles have enabled the classification of head and neck squamous cell carcinoma (HNSCC) into molecular sub-types and provide prognostic information, which have implications for the personalized treatment of HNSCC beyond clinical and pathological features. Methods: Gene-expression profiling was identified in TCGA- HNSCC (n = 492) and validated with the Gene Expression Ominibus (GEO) dataset(n = 270) for which RNA sequencing data and clinical covariates were available. A single-sample gene set enrichment analysis (ssGSEA) algorithm were used to quantified the levels of various hallmarks of cancer. And LASSO Cox regression model was used to screen robust prognostic biomarkers to identify the best set of survival-associated gene signatures in HNSCC. Statistical analyses were performed using R version 3.4.4. Results: We identified unfolded protein response as the primary risk factor for survival（cox coefficient = 17.4 [8.4-26.3], P < 0.001）among various hallmarks of cancer in TCGA- HNSCC. And unfolded protein response ssGESA scores were significantly elevated in patients who died during follow up (P = 0.009). Kaplan-Meier analysis showed that patients with low ssGSEA scores of unfolded protein response exhibited better OS (HR = 0.69, P = 0.008). And we established an unfolded protein response-related gene signature based on lasso cox. We then apply the unfolded protein response -related gene signature to classify patients into the high risk group and the low risk group with the cutoff of 0.18. Adjusted for stage，age，gender, our signature was an independent risk factor for overall survival in TCGA cohorts (HR = 0.39 [0.28-0.53],P = < 0.001). In external independent cohorts, similar results were observed. In the validation cohort GEO65858, the patients with high unfolded protein response score showed longer survival (HR = 0.62 [0.38-1.0], P = 0.049). And adjusted for stage，age，HPV state, the multivariate cox regression analysis showed that unfolded protein response-related gene signature exhibited an independent risk prediction for overall survival in 270 patients with HNSCC (HR = 0.57 [0.35-0.94], P = 0.026). Conclusions: By analyzing the gene-expression data with bioinformation approach, we developed and validated a risk prediction model with unfolded protein response -related expression scores in HNSCC, which have the potential to identify patients who could have better overall survival.

scholarly journals Transcriptome Analysis of Recombinant Protein Secretion by Aspergillus nidulans and the Unfolded-Protein Response In Vivo

2005 ◽  
Vol 71 (5) ◽  
pp. 2737-2747 ◽  
Author(s):  
Andrew H. Sims ◽  
Manda E. Gent ◽  
Karin Lanthaler ◽  
Nigel S. Dunn-Coleman ◽  
Stephen G. Oliver ◽  
...  
Keyword(s):  
Gene Expression ◽  
Recombinant Protein ◽  
Unfolded Protein Response ◽  
Aspergillus Nidulans ◽  
Filamentous Fungi ◽  
Protein Secretion ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACT Filamentous fungi have a high capacity for producing large amounts of secreted proteins, a property that has been exploited for commercial production of recombinant proteins. However, the secretory pathway, which is key to the production of extracellular proteins, is rather poorly characterized in filamentous fungi compared to yeast. We report the effects of recombinant protein secretion on gene expression levels in Aspergillus nidulans by directly comparing a bovine chymosin-producing strain with its parental wild-type strain in continuous culture by using expressed sequence tag microarrays. This approach demonstrated more subtle and specific changes in gene expression than those observed when mimicking the effects of protein overproduction by using a secretion blocker. The impact of overexpressing a secreted recombinant protein more closely resembles the unfolded-protein response in vivo.

scholarly journals Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the unfolded protein response (UPR) in models of neurodegeneration

2020 ◽  
Author(s):  
René L. Vidal ◽  
Denisse Sepulveda ◽  
Paulina Troncoso-Escudero ◽  
Paula Garcia-Huerta ◽  
Constanza Gonzalez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Unfolded Protein Response ◽  
Target Genes ◽  
Cell Function ◽  
Alpha Synuclein ◽  
Protective Effects ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractAlteration to endoplasmic reticulum (ER) proteostasis is observed on a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR-target genes. Here, we designed an ATF6f-XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has stronger an effect in reducing the abnormal aggregation of mutant huntingtin and alpha-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson’s and Huntington’s disease. These results support the concept where directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.

scholarly journals A pilot study on gene expression of endoplasmic reticulum unfolded protein response in chronic kidney disease

2020 ◽  
Vol 24 ◽  
pp. 100829
Author(s):  
Rasha G. Mostafa ◽  
Abd El-Aleem Hassan Abd El-Aleem ◽  
Eman Abdella Mahmoud Fouda ◽  
Fardous Rabea Ahmed Taha ◽  
Khaled Mohamed Amin Elzorkany
Keyword(s):  
Gene Expression ◽  
Chronic Kidney Disease ◽  
Endoplasmic Reticulum ◽  
Pilot Study ◽  
Kidney Disease ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Protein Response

scholarly journals Activation of the Unfolded Protein Response Pathway Induces Human Asparagine Synthetase Gene Expression

1999 ◽  
Vol 274 (44) ◽  
pp. 31139-31144 ◽  
Author(s):  
Ione P. Barbosa-Tessmann ◽  
Chin Chen ◽  
Can Zhong ◽  
Sheldon M. Schuster ◽  
Harry S. Nick ◽  
...  
Keyword(s):  
Gene Expression ◽  
Unfolded Protein Response ◽  
Asparagine Synthetase ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Blunted activation of NF-κB and NF-κB-dependent gene expression by geranylgeranylacetone: Involvement of unfolded protein response

2008 ◽  
Vol 365 (1) ◽  
pp. 47-53 ◽  
Author(s):  
Kunihiro Hayakawa ◽  
Nobuhiko Hiramatsu ◽  
Maro Okamura ◽  
Jian Yao ◽  
Adrienne W. Paton ◽  
...  
Keyword(s):  
Gene Expression ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Protein Response

scholarly journals Angiogenesis Induced By Aminoacyl-tRNA Synthetase Deficiency Is Dependent on Amino Acid Response (AAR) but Not Unfolded Protein Response (UPR) Pathways

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 77-77
Author(s):  
Fan Zhang ◽  
Yi Chen ◽  
Yi Jin ◽  
Chun-Hui Xu ◽  
Dian-Jia Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Amino Acid ◽  
Stress Response ◽  
Unfolded Protein Response ◽  
Blood Vessels ◽  
Protein Translation ◽  
Trna Synthetase ◽  
Unfolded Protein ◽  
Protein Response ◽  
Amino Acid Response

Abstract Stress-induced angiogenesis enormously contributes to both normal development and pathogenesis of various diseases including cancer. Among many stress response pathways implicated in regulation of angiogenesis, the amino acid response (AAR) and the unfolded protein response (UPR) pathways are closely interconnected, as they converge on the common target, eIF2α, which is a key regulator of protein translation. Two kinases, namely Gcn2 (Eif2ak4) and Perk (Eif2ak3), are responsible for transducing signals from AAR and UPR, respectively, to phosphorylation of eIF2α. Even though numerous studies have been performed, this close interconnection between AAR and UPR makes it difficult to clearly distinguish different contributions of these two pathways in regulation of angiogenesis. In this study, we generated a zebrafish angiogenic model harboring a loss-of-function mutation of the threonyl-tRNA synthetase (tars) gene. Tars belongs to a family of evolutionarily conserved enzymes, aminoacyl-tRNA synthetases (aaRSs), which control the first step of protein translation through coupling specific amino acids with their cognate tRNAs. Deficiencies of several aaRSs in zebrafish have been shown to cause increased branching of blood vessels, and this angiogenic phenotype has roughly been explained by activation of AAR and UPR; however, it is unclear whether both AAR and UPR are required and to what extent they contribute to this process. To address this issue, we first performed RNA-seq analyses of Tars-mutated and control zebrafish embryos, as well as those with knockdown of either Gcn2 or Perk in both genotypes. We found that the AAR target genes are dramatically activated in the Tars-mutants, whereas the genes associated with the three UPR sub-pathways (i.e., Perk-, Ire1- and Atf6-mediated pathways) remain inactive, except for very few genes (e.g., Atf3, Atf4, Asns and Igfbp1) that are shared in both AAR and UPR, thus suggesting activation of AAR, but not UPR, in the Tars-mutants. In support of this notion, knockdown of the AAR-associated kinase Gcn2 in the Tars-mutants largely represses the activated genes, while the Perk knockdown shows very little effect. Nonetheless, in contrast to the apparently dispensable role of Perk in Tars-mutants, knockdown of Perk in control embryos leads to specific gene expression alterations, suggesting that Perk effectively functions in homeostatic states (i.e., controls), but, in the stress condition (i.e., Tars-mutants), its function is largely overwhelmed by activation of the Gcn2-mediated AAR. To validate these observations, we investigated the angiogenic phenotypes of the zebrafish models upon genetic and pharmacological interference with the AAR and UPR pathways. A transgenic zebrafish line, Tg(flk1:EGFP), was crossed with the Tars-mutants to visualize angiogenesis in vivo. We observed increased branching of blood vessels in the Tars-mutants, which is rescued by tars mRNA but not an enzymatically dead version. Importantly, knockdown of Gcn2 in the Tars-mutants rescues this phenotype. In contrast, knockdown of Perk, or knockdown of two other known eIF2α kinases, Hri (Eif2ak1) or Pkr (Eif2ak2), shows no effect. Furthermore, knockdown of either one of two major factors downstream to eIF2α, namely Atf4 and Vegfα, or inhibition of Vegf receptor with the drug SU5416, also rescue the phenotype. Thus, these results confirm that AAR, but not UPR, is required for the Tars-deficiency-induced angiogenesis. Taken together, this study demonstrates that, despite being closely interconnected and even sharing a common downstream target, the Gcn2-mediated AAR and the Perk-mediated UPR can be activated independently in different conditions and differentially regulate cellular functions such as angiogenesis. This notion reflects the specificity and efficiency of multiple stress response pathways that are evolved integrally to benefit the organism by ensuring sensing and responding precisely to different types of stresses. This study also provides an example of combining systematic gene expression profiling and phenotypic validations to distinguish activities of such interconnected pathways. Further clarification of the mechanisms shall advance our understanding of how the organisms respond to diverse stresses and how the abnormalities in these regulatory machineries cause cellular stress-related diseases such as cancer, diabetes and immune disorders. Disclosures No relevant conflicts of interest to declare.

scholarly journals Identification of a novel signature based on unfolded protein response-related gene for predicting prognosis in bladder cancer

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Ke Zhu ◽  
Liu Xiaoqiang ◽  
Wen Deng ◽  
Gongxian Wang ◽  
Bin Fu
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Unfolded Protein Response ◽  
Immune Cells ◽  
Risk Groups ◽  
Immune Checkpoints ◽  
Related Gene ◽  
Prognostic Signature ◽  
Unfolded Protein ◽  
Protein Response

Abstract Background The unfolded protein response (UPR) served as a vital role in the progression of tumors, but the molecule mechanisms of UPR in bladder cancer (BLCA) have been not fully investigated. Methods We identified differentially expressed unfolded protein response-related genes (UPRRGs) between BLCA samples and normal bladder samples in the Cancer Genome Atlas (TCGA) database. Univariate Cox analysis and the least absolute shrinkage and selection operator penalized Cox regression analysis were used to construct a prognostic signature in the TCGA set. We implemented the validation of the prognostic signature in GSE13507 from the Gene Expression Omnibus database. The ESTIMATE, CIBERSORT, and ssGSEA algorithms were used to explore the correlation between the prognostic signature and immune cells infiltration as well as key immune checkpoints (PD-1, PD-L1, CTLA-4, and HAVCR2). GDSC database analyses were conducted to investigate the chemotherapy sensitivity among different groups. GSEA analysis was used to explore the potential mechanisms of UPR-based signature. Results A prognostic signature comprising of seven genes (CALR, CRYAB, DNAJB4, KDELR3, CREB3L3, HSPB6, and FBXO6) was constructed to predict the outcome of BLCA. Based on the UPRRGs signature, the patients with BLCA could be classified into low-risk groups and high-risk groups. Patients with BLCA in the low-risk groups showed the more favorable outcomes than those in the high-risk groups, which was verified in GSE13507 set. This signature could serve as an autocephalous prognostic factor in BLCA. A nomogram based on risk score and clinical characteristics was established to predict the over survival of BLCA patients. Furthermore, the signature was closely related to immune checkpoints (PD-L1, CTLA-4, and HAVCR2) and immune cells infiltration including CD8+ T cells, follicular helper T cells, activated dendritic cells, and M2 macrophages. GSEA analysis indicated that immune and carcinogenic pathways were enriched in high-risk group. Conclusions We identified a novel unfolded protein response-related gene signature which could predict the over survival, immune microenvironment, and chemotherapy response of patients with bladder cancer.

scholarly journals Repression of Viral Gene Expression and Replication by the Unfolded Protein Response Effector XBP1u

2019 ◽  
Author(s):  
Florian Hinte ◽  
Eelco van Anken ◽  
Boaz Tirosh ◽  
Wolfram Brune
Keyword(s):  
Gene Expression ◽  
Life Cycle ◽  
Unfolded Protein Response ◽  
Viral Gene Expression ◽  
Murine Cytomegalovirus ◽  
Viral Gene ◽  
Unfolded Protein ◽  
Xbp1 Mrna ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractThe unfolded protein response (UPR) is a cellular homeostatic circuit regulating protein synthesis and processing in the ER by three ER-to-nucleus signaling pathways. One pathway is triggered by the inositol-requiring enzyme 1 (IRE1), which splices the X-box binding protein 1 (XBP1) mRNA, thereby enabling expression of XBP1s. Another UPR pathway activates the activating transcription factor 6 (ATF6). Here we show that murine cytomegalovirus (MCMV), a prototypic β-herpesvirus, harnesses the UPR to regulate its own life cycle. MCMV activates the IRE1-XBP1 pathway early post infection to relieve repression by XBP1u, the product of the unspliced XBP1 mRNA. XBP1u inhibits viral gene expression and replication by blocking the activation of the viral major immediate-early promoter by XBP1s and ATF6. These findings reveal a redundant function of XBP1s and ATF6 as activators of the viral life cycle, and an unexpected role of XBP1u as a potent repressor of both XBP1s and ATF6-mediated activation.

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