The Unfolded Protein Response and Cell Fate Control

Hetz, Claudio; Papa, Feroz R.

doi:10.1016/j.molcel.2017.06.017

Cited by 1,057 publications

(1,062 citation statements)

References 126 publications

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“…In human β‐cells, the expression of different UPR genes and chaperones is high, suggesting that β‐cells are well equipped to cope with rapid fluctuations in proinsulin synthesis and with the generation of misfolded proteins . When activation of the UPR fails to correct protein folding, it may eventually lead to apoptosis, a process called “terminal UPR.” The latter is mediated via stress kinases, such as JNK and transcription factors including CHOP/GADD153 and ATF3 . In addition, ER stress‐induced IRE1α oligomerization has been shown to increase thioredoxin‐interacting protein (TxNIP) expression with subsequent activation of the NLRP3 inflammasome and caspase‐1‐dependent pro‐death pathway .…”

Section: β‐Cell Adaptation To Proinsulin Misfoldingmentioning

confidence: 99%

Effects of proinsulin misfolding on β‐cell dynamics, differentiation and function in diabetes

Riahi

Israeli

Cerasi

et al. 2018

Diabetes Obesity Metabolism

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ER stress due to proinsulin misfolding has an important role in the pathophysiology of rare forms of permanent neonatal diabetes (PNDM) and probably also of common type 1 (T1D) and type 2 diabetes (T2D). Accumulation of misfolded proinsulin in the ER stimulates the unfolded protein response (UPR) that may eventually lead to apoptosis through a process called the terminal UPR. However, the β-cell ER has an incredible ability to cope with accumulation of misfolded proteins; therefore, it is not clear whether in common forms of diabetes the accumulation of misfolded proinsulin exceeds the point of no return in which terminal UPR is activated. Many studies showed that the UPR is altered in both T1D and T2D; however, the observed changes in the expression of different UPR markers are inconsistent and it is not clear whether they reflect an adaptive response to stress or indeed mediate the β-cell dysfunction of diabetes. Herein, we critically review the literature on the effects of proinsulin misfolding and ER stress on β-cell dysfunction and loss in diabetes with emphasis on β-cell dynamics, and discuss the gaps in understanding the role of proinsulin misfolding in the pathophysiology of diabetes.

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Section: β‐Cell Adaptation To Proinsulin Misfoldingmentioning

confidence: 99%

Effects of proinsulin misfolding on β‐cell dynamics, differentiation and function in diabetes

Riahi

Israeli

Cerasi

et al. 2018

Diabetes Obesity Metabolism

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“…ER stress is usually induced during tumor development and progression, becoming a hallmark of such malignancies . Although the unfolded protein response (UPR) program is primarily a prosurvival process, sustained and/or prolonged stress may result in cell death induction . Therefore, understanding the role of ERS in the induction of cucurbitacin‐I in the cancer cell death may be crucial to specifically reveal the mechanism of cucurbitacin‐I and avoid its potential resistance.…”

Section: Introductionmentioning

confidence: 99%

Cucurbitacin I induces cancer cell death through the endoplasmic reticulum stress pathway

Chen

et al. 2018

J of Cellular Biochemistry

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Endoplasmic reticulum stress (ERS) is usually involved in tumor development and progression, and anticancer agents have recently been recognized to induce ERS. Cucurbitacin‐I showed a potent anticancer action by inducing apoptosis through the inhibition of signal transducer and activator of transcription 3 pathway and triggering autophagic cell death. It is not known whether ERS mediates the cancer cell death induced by cucurbitacin‐I. Here, we investigated the role of ERS in cucurbitacin‐I‐treated SKOV3 ovarian cancer cells and PANC‐1 pancreatic cancer cells. We confirmed that cucurbitacin‐I caused cell death and stirred excessive ERS levels by activating inositol requiring enzyme 1α (IRE1α) and protein kinase R‐like endoplasmic reticulum kinase (PERK), as well as PERK downstream factors, including IRE1α and C/EBP homologous protein, but not activating transcription factor 6 (ATF6α) pathway, which was in parallel with the increased Bax and caspase‐12‐dependent ERS‐associated apoptosis, autophagy and autophagy flux levels and caspase‐independent nonapoptotic cell death. Furthermore, 4‐phenylbutyrate, an ERS inhibitor, suppressed cucurbitacin‐I‐induced apoptosis, autophagy, autophagy flux, and autophagic cell death. Simultaneously, there are positive correlations among ERS and cucurbitacin‐I‐induced reactive oxygen species and Ca 2+. Our results suggested that cucurbitacin‐I‐induced cancer cell death through the excessive ERS and CHOP‐Bax and caspase‐12‐dependent ERS‐associated apoptosis, as well as ERS‐dependent autophagy, autophagy flux, and caspase‐independent nonapoptotic cell death. These novel signaling insights may be useful for developing new, effective anticancer strategies in oncotherapy.

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“…This is an indication of ER stress, which typically induces the unfolded protein response (UPR) in order to improve the imbalance between protein load and folding capacity of the ER (Hori et al, 2006;Hetz and Papa, 2017).…”

Section: Discussionmentioning

confidence: 99%

Environmental Stress Responses and Experimental Handling Artifacts of a Model Organism, the Copepod Acartia tonsa (Dana)

et al. 2018

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Handling animals during experiments potentially affects the differential expression of genes chosen as biomarkers of sub-lethal stress. RNA sequencing was used to examine whole-transcriptome responses caused by laboratory handling of the calanoid copepod, Acartia tonsa. Salinity shock (S = 35 to S = 5) was used as positive stress control; individuals not exposed to handling or other stressors served as negative stress control. All copepods were grown from eggs to adults without being handled or exposed to any stressors prior the experiment. Survival of nauplii and adults was estimated for up to 10 min of exposure to handling stress and salinity shock. Only adults exhibited decreased survival (44 ± 7% with 10 min of exposure) in response to handling stress and were selected for definitive experiments for RNA sequencing. After 10 min of experimental exposures to handling stress or salinity shock, adults were incubated for 15 min or 24 h at normal culture conditions. A small number of significantly differentially expressed genes (DEGs) were observed 15 min after exposure to handling stress (2 DEGs) or salinity shock (7 DEGs). However, 24 h after exposure, handling stress resulted in 276 DEGs and salinity shock resulted in 573 DEGs, of which 174 DEGs were overlapping between the treatments. Among the DEGs observed 24 h after exposure to handling stress or salinity shock, some commonly-used stress biomarkers appeared at low levels. This suggests that a stress-response was induced at the transcriptional level for these genes between 15 min and 24 h following exposure. Since handling stress clearly affects transcriptional patterns, it is important to consider handling when designing experiments, by either including additional controls or avoiding focus on impacted genes. Not considering handling in gene expression studies can lead to inaccurate conclusions. The present study provides a baseline for studying handling stress in future studies using this model organism and others.

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The Unfolded Protein Response and Cell Fate Control

Cited by 1,057 publications

References 126 publications

Effects of proinsulin misfolding on β‐cell dynamics, differentiation and function in diabetes

Effects of proinsulin misfolding on β‐cell dynamics, differentiation and function in diabetes

Cucurbitacin I induces cancer cell death through the endoplasmic reticulum stress pathway

Environmental Stress Responses and Experimental Handling Artifacts of a Model Organism, the Copepod Acartia tonsa (Dana)

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