scholarly journals GRP78/BiP determines senescence evasion cell fate after cisplatin-based chemotherapy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zin Zin Ei ◽  
Kanuengnit Choochuay ◽  
Alisa Tubsuwan ◽  
Decha Pinkaew ◽  
Maneewan Suksomtip ◽  
...  
Keyword(s):  
Cell Fate ◽  
Translational Regulation ◽  
Genetic Manipulation ◽  
A549 Cells ◽  
Cancer Subtypes ◽  
Guide Rna ◽  
Protein Levels ◽  
Unfolded Protein ◽  
H460 Cells ◽  
The Unfolded Protein Response

AbstractCisplatin (CDDP) induces senescence characterized by senescence-associated secretory phenotypes (SASP) and the unfolded protein response (UPR). In this study, we investigated the proteins related to the UPR during the senescence cell fate. Strikingly, we found that one of the critical ER-resident proteins, GRP78/BiP, was significantly altered. Here we show that GRP78 levels differentially expressed depending on non-small lung cancer subtypes. GRP78 indeed regulates the evasion of senescence in adenocarcinoma A549 cells, in which the increased GRP78 levels enable them to re-proliferate after CDDP removal. Conversely, GRP78 is downregulated in the senescence H460 cells, making them lacking senescence evasion capability. We observed that the translational regulation critically contributed to the GRP78 protein levels in CDDP-induces senescence. Furthermore, the increased GRP78 level during senescence confers resistance to senolytic drug, Bortezomib, as observed by a twofold increase in IC50 in A549 senescence cells compared to the wild-type. This observation is also consistent in the cells that have undergone genetic manipulation by transfection with pcDNA3.1(+)-GRP78/BiP plasmids and pSpCas9(BB)-2A-Puro containing guide RNA sequence targeting GRP78 exon 3 to induce the overexpression and downregulation of GRP78 in H460 cells, respectively. Our findings reveal a unique role of GRP78 on the senescence evasion cell fate and senolytic drug resistance after cisplatin-based chemotherapy.

scholarly journals Comprehensive Analysis of the Unfolded Protein Response in Breast Cancer Subtypes

2017 ◽  
pp. 1-9 ◽  
Author(s):  
Dadi Jiang ◽  
Brandon Turner ◽  
Jie Song ◽  
Ruijiang Li ◽  
Maximilian Diehn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Patient Survival ◽  
Gene Signature ◽  
Comprehensive Analysis ◽  
Breast Cancer Subtypes ◽  
Cancer Subtypes ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Purpose Triple-negative breast cancers (TNBCs) are associated with a worse prognosis and patients with TNBC have fewer therapeutic options than patients with non-TNBC. Recently, the IRE1α-XBP1 branch of the unfolded protein response (UPR) was implicated in TNBC prognosis on the basis of a relatively small patient population, suggesting the diagnostic and therapeutic value of this pathway in TNBCs. In addition, the IRE1α-XBP1 and hypoxia-induced factor 1 α (HIF1α) pathways have been identified as interacting partners in TNBC, suggesting a novel mechanism of regulation. To comprehensively evaluate and validate these findings, we investigated the relative activities and relevance to patient survival of the UPR and HIF1α pathways in different breast cancer subtypes in large populations of patients. Materials and Methods We performed a comprehensive analysis of gene expression and survival data from large cohorts of patients with breast cancer. The patients were stratified based on the average expression of the UPR or HIF1α gene signatures. Results We identified a strong positive association between the XBP1 gene signature and estrogen receptor–positive status or the HIF1α gene signature, as well as the predictive value of the XBP1 gene signature for survival of patients who are estrogen receptor negative, or have TNBC or HER2+. In contrast, another important UPR branch, the ATF4/CHOP pathway, lacks prognostic value in breast cancer in general. Activity of the HIF1α pathway is correlated with patient survival in all the subtypes evaluated. Conclusion These findings clarify the relevance of the UPR pathways in different breast cancer subtypes and underscore the potential therapeutic importance of the IRE1α-XBP1 branch in breast cancer treatment.

scholarly journals ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eun-Jin Lee ◽  
Priscilla Chan ◽  
Leon Chea ◽  
Kyle Kim ◽  
Randal J. Kaufman ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Retinal Degeneration ◽  
Mrna Levels ◽  
Photoreceptor Layer ◽  
Protein Levels ◽  
Unfolded Protein ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractRetinitis Pigmentosa (RP) is a blinding disease that arises from loss of rods and subsequently cones. The P23H rhodopsin knock-in (P23H-KI) mouse develops retinal degeneration that mirrors RP phenotype in patients carrying the orthologous variant. Previously, we found that the P23H rhodopsin protein was degraded in P23H-KI retinas, and the Unfolded Protein Response (UPR) promoted P23H rhodopsin degradation in heterologous cells in vitro. Here, we investigated the role of a UPR regulator gene, activating transcription factor 6 (Atf6), in rhodopsin protein homeostasis in heterozygous P23H rhodopsin (Rho+/P23H) mice. Significantly increased rhodopsin protein levels were found in Atf6−/−Rho+/P23H retinas compared to Atf6+/−Rho+/P23H retinas at early ages (~ P12), while rhodopsin mRNA levels were not different. The IRE1 pathway of the UPR was hyper-activated in young Atf6−/−Rho+/P23H retinas, and photoreceptor layer thickness was unchanged at this early age in Rho+/P23H mice lacking Atf6. By contrast, older Atf6−/−Rho+/P23H mice developed significantly increased retinal degeneration in comparison to Atf6+/−Rho+/P23H mice in all retinal layers, accompanied by reduced rhodopsin protein levels. Our findings demonstrate that Atf6 is required for efficient clearance of rhodopsin protein in rod photoreceptors expressing P23H rhodopsin, and that loss of Atf6 ultimately accelerates retinal degeneration in P23H-KI mice.

scholarly journals Reduced Paneth cell antimicrobial protein levels correlate with activation of the unfolded protein response in the gut of obese individuals

2011 ◽  
Vol 225 (2) ◽  
pp. 276-284 ◽  
Author(s):  
Caroline M Hodin ◽  
Froukje J Verdam ◽  
Joep Grootjans ◽  
Sander S Rensen ◽  
Fons K Verheyen ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Paneth Cell ◽  
Antimicrobial Protein ◽  
Protein Levels ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

scholarly journals Ribosomal mistranslation leads to silencing of the unfolded protein response and increased mitochondrial biogenesis

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Dmitri Shcherbakov ◽  
Youjin Teo ◽  
Heithem Boukari ◽  
Adrian Cortes-Sanchon ◽  
Matilde Mantovani ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Mitochondrial Biogenesis ◽  
Protein Quality ◽  
Genetic Manipulation ◽  
Ubiquitin Proteasome System ◽  
Limiting Factor ◽  
Unfolded Protein ◽  
Comprehensive Picture ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Translation fidelity is the limiting factor in the accuracy of gene expression. With an estimated frequency of 10−4, errors in mRNA decoding occur in a mostly stochastic manner. Little is known about the response of higher eukaryotes to chronic loss of ribosomal accuracy as per an increase in the random error rate of mRNA decoding. Here, we present a global and comprehensive picture of the cellular changes in response to translational accuracy in mammalian ribosomes impaired by genetic manipulation. In addition to affecting established protein quality control pathways, such as elevated transcript levels for cytosolic chaperones, activation of the ubiquitin-proteasome system, and translational slowdown, ribosomal mistranslation led to unexpected responses. In particular, we observed increased mitochondrial biogenesis associated with import of misfolded proteins into the mitochondria and silencing of the unfolded protein response in the endoplasmic reticulum.

scholarly journals Ero1L, a thiol oxidase, is required for Notch signaling through cysteine bridge formation of the Lin12-Notch repeats in Drosophila melanogaster

2008 ◽  
Vol 182 (6) ◽  
pp. 1113-1125 ◽  
Author(s):  
An-Chi Tien ◽  
Akhila Rajan ◽  
Karen L. Schulze ◽  
Hyung Don Ryoo ◽  
Melih Acar ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Notch Signaling ◽  
Cell Fate ◽  
Disulfide Bonds ◽  
Cell Communication ◽  
Notch Receptor ◽  
Cell Fate Decisions ◽  
Unfolded Protein ◽  
Thiol Oxidase ◽  
The Unfolded Protein Response

Notch-mediated cell–cell communication regulates numerous developmental processes and cell fate decisions. Through a mosaic genetic screen in Drosophila melanogaster, we identified a role in Notch signaling for a conserved thiol oxidase, endoplasmic reticulum (ER) oxidoreductin 1–like (Ero1L). Although Ero1L is reported to play a widespread role in protein folding in yeast, in flies Ero1L mutant clones show specific defects in lateral inhibition and inductive signaling, two characteristic processes regulated by Notch signaling. Ero1L mutant cells accumulate high levels of Notch protein in the ER and induce the unfolded protein response, suggesting that Notch is misfolded and fails to be exported from the ER. Biochemical assays demonstrate that Ero1L is required for formation of disulfide bonds of three Lin12-Notch repeats (LNRs) present in the extracellular domain of Notch. These LNRs are unique to the Notch family of proteins. Therefore, we have uncovered an unexpected requirement for Ero1L in the maturation of the Notch receptor.

scholarly journals Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor

Blood ◽  
2007 ◽  
Vol 110 (10) ◽  
pp. 3610-3617 ◽  
Author(s):  
Jens Köditz ◽  
Jutta Nesper ◽  
Marieke Wottawa ◽  
Daniel P. Stiehl ◽  
Gieri Camenisch ◽  
...  
Keyword(s):  
Cell Fate ◽  
Oxygen Sensor ◽  
Hypoxia Inducible Factor ◽  
Adaptive Responses ◽  
Von Hippel Lindau ◽  
Cell Fate Decisions ◽  
Protein Levels ◽  
Activating Transcription Factor 4 ◽  
Domain 3 ◽  
The Unfolded Protein Response

Abstract The activating transcription factor-4 (ATF-4) is translationally induced under anoxic conditions, mediates part of the unfolded protein response following endoplasmic reticulum (ER) stress, and is a critical regulator of cell fate. Here, we identified the zipper II domain of ATF-4 to interact with the oxygen sensor prolyl-4-hydroxylase domain 3 (PHD3). The PHD inhibitors dimethyloxalylglycine (DMOG) and hypoxia, or proteasomal inhibition, all induced ATF-4 protein levels. Hypoxic induction of ATF-4 was due to increased protein stability, but was independent of the ubiquitin ligase von Hippel–Lindau protein (pVHL). A novel oxygen-dependent degradation (ODD) domain was identified adjacent to the zipper II domain. Mutations of 5 prolyl residues within this ODD domain or siRNA-mediated down-regulation of PHD3, but not of PHD2, was sufficient to stabilize ATF-4 under normoxic conditions. These data demonstrate that PHD-dependent oxygen-sensing recruits both the hypoxia-inducible factor (HIF) and ATF-4 systems, and hence not only confers adaptive responses but also cell fate decisions.

scholarly journals The unfolded protein response in relation to mitochondrial biogenesis in skeletal muscle cells

2017 ◽  
Vol 312 (5) ◽  
pp. C583-C594 ◽  
Author(s):  
Zahra S. Mesbah Moosavi ◽  
David A. Hood
Keyword(s):  
Er Stress ◽  
Mitochondrial Biogenesis ◽  
Contractile Activity ◽  
Muscle Cells ◽  
Unfolded Proteins ◽  
Protein Levels ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Mitochondrial Adaptations

Mitochondria comprise both nuclear and mitochondrially encoded proteins requiring precise stoichiometry for their integration into functional complexes. The augmented protein synthesis associated with mitochondrial biogenesis results in the accumulation of unfolded proteins, thus triggering cellular stress. As such, the unfolded protein responses emanating from the endoplasmic reticulum (UPRER) or the mitochondrion (UPRMT) are triggered to ensure correct protein handling. Whether this response is necessary for mitochondrial adaptations is unknown. Two models of mitochondrial biogenesis were used: muscle differentiation and chronic contractile activity (CCA) in murine muscle cells. After 4 days of differentiation, our findings depict selective activation of the UPRMTin which chaperones decreased; however, Sirt3 and UPRERmarkers were elevated. To delineate the role of ER stress in mitochondrial adaptations, the ER stress inhibitor TUDCA was administered. Surprisingly, mitochondrial markers COX-I, COX-IV, and PGC-1α protein levels were augmented up to 1.5-fold above that of vehicle-treated cells. Similar results were obtained in myotubes undergoing CCA, in which biogenesis was enhanced by ~2–3-fold, along with elevated UPRMTmarkers Sirt3 and CPN10. To verify whether the findings were attributable to the terminal UPRERbranch directed by the transcription factor CHOP, cells were transfected with CHOP siRNA. Basally, COX-I levels increased (~20%) and COX-IV decreased (~30%), suggesting that CHOP influences mitochondrial composition. This effect was fully restored by CCA. Therefore, our results suggest that mitochondrial biogenesis is independent of the terminal UPRER. Under basal conditions, CHOP is required for the maintenance of mitochondrial composition, but not for differentiation- or CCA-induced mitochondrial biogenesis.

scholarly journals Structural and Functional Significance of the Endoplasmic Reticulum Unfolded Protein Response Transducers and Chaperones at the Mitochondria–ER Contacts: A Cancer Perspective

2021 ◽  
Vol 9 ◽  
Author(s):  
Giuseppina Amodio ◽  
Valentina Pagliara ◽  
Ornella Moltedo ◽  
Paolo Remondelli
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Cell Fate ◽  
Tumor Development ◽  
Unfolded Protein ◽  
Mitochondria Dynamics ◽  
Fate Decision ◽  
The Unfolded Protein Response ◽  
Almost All ◽  
Protein Response

In the last decades, the endoplasmic reticulum (ER) has emerged as a key coordinator of cellular homeostasis, thanks to its physical interconnection to almost all intracellular organelles. In particular, an intense and mutual crosstalk between the ER and mitochondria occurs at the mitochondria–ER contacts (MERCs). MERCs ensure a fine-tuned regulation of fundamental cellular processes, involving cell fate decision, mitochondria dynamics, metabolism, and proteostasis, which plays a pivotal role in the tumorigenesis and therapeutic response of cancer cells. Intriguingly, recent studies have shown that different components of the unfolded protein response (UPR) machinery, including PERK, IRE1α, and ER chaperones, localize at MERCs. These proteins appear to exhibit multifaceted roles that expand beyond protein folding and UPR transduction and are often related to the control of calcium fluxes to the mitochondria, thus acquiring relevance to cell survival and death. In this review, we highlight the novel functions played by PERK, IRE1α, and ER chaperones at MERCs focusing on their impact on tumor development.

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