Multiple Mechanisms of Unfolded Protein Response–Induced Cell Death

Hiramatsu, Naoki; Chiang, Wei‐Chieh; Kurt, Timothy D.; Sigurdson, Christina J.; Lin, Jonathan H.

doi:10.1016/j.ajpath.2015.03.009

Cited by 160 publications

(156 citation statements)

References 87 publications

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“…The inability of cells to remove damaged proteins from the ER for a prolonged period of time triggers an apoptotic cell death pathway (Hiramatsu et al, 2015;Song et al, 2017). A similar observation was made in vitro when cells were exposed to high levels of oxidised amino acids to generate oxidised proteins (Dunlop et al, 2008) suggesting that oxidised proteins can also trigger apoptotic cell death in a similar way.…”

Section: Resultssupporting

confidence: 50%

Oxidised protein metabolism: recent insights

Samardzic

Rodgers

2017

Biological Chemistry

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Abstract:The 'oxygen paradox' arises from the fact that oxygen, the molecule that aerobic life depends on, threatens its very existence. An oxygen-rich environment provided life on Earth with more efficient bioenergetics and, with it, the challenge of having to deal with a host of oxygen-derived reactive species capable of damaging proteins and other crucial cellular components. In this minireview, we explore recent insights into the metabolism of proteins that have been reversibly or irreversibly damaged by oxygen-derived species. We discuss recent data on the important roles played by the proteasomal and lysosomal systems in the proteolytic degradation of oxidatively damaged proteins and the effects of oxidative damage on the function of the proteolytic pathways themselves. Mitochondria are central to oxygen utilisation in the cell, and their ability to handle oxygen-derived radicals is an important and still emerging area of research. Current knowledge of the proteolytic machinery in the mitochondria, including the ATPdependent AAA+ proteases and mitochondrial-derived vesicles, is also highlighted in the review. Significant progress is still being made in regard to understanding the mechanisms underlying the detection and degradation of oxidised proteins and how proteolytic pathways interact with each other. Finally, we highlight a few unanswered questions such as the possibility of oxidised amino acids released from oxidised proteins by proteolysis being re-utilised in protein synthesis thus establishing a vicious cycle of oxidation in cells.

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Section: Resultssupporting

confidence: 50%

Oxidised protein metabolism: recent insights

Samardzic

Rodgers

2017

Biological Chemistry

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“…23 CHOP and caspase 12 function as the main mediators mediating ERS-induced apoptosis, and many factors ameliorate apoptosis in cardiomyocytes through inhibiting the upregulation of CHOP [24][25][26] or the activation of caspase 12.…”

Section: Discussionmentioning

confidence: 99%

“…To restore the homeostasis of ER, ERS triggers a series of accommodative mechanisms known as the unfolded protein response (UPR), including attenuation of translation, elevated expression of ER chaperones and associated proteins, and degradation of unfolded/misfolded proteins by quality-control system. 1 However, when the ER function is seriously damaged, ERS stimulates apoptotic signals pathway, 2,3 which has been implicated in many cardiovascular pathological processes such as ischemic heart disease, atherosclerosis, myocardial ischemia/reperfusion (I/R) injury, cardiomyopathy, and heart failure. 4 Previous study has demonstrated that ERS contributed to myocardial injury, and some factors also improved impairment of myocardium by inhibiting ERS.…”

Section: Introductionmentioning

confidence: 99%

Tanshinone IIA ameliorates apoptosis of cardiomyocytes induced by endoplasmic reticulum stress

Feng

Chen

2016

Exp Biol Med (Maywood)

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The fat-soluble diterpenoids tanshinone IIA (TSA) is the major active element of Danshen, which has widespread cardioprotective effect. However, the mechanism of its beneficial effect on cardiomyocytes has not been fully investigated. Here, we aim to demonstrate that TSA ameliorates apoptosis of cardiomyocytes activated by endoplasmic reticulum stress (ERS). Primary cultures of neonatal rat cardiomyocytes are used, in which ERS-mediated apoptosis is induced by tunicamycin (Tm). Apoptosis of cardiomyocytes are detected by Hoechst staining and caspase 3 activity analysis. Protein expression of ERS markers are detected by Western blot, and level of miroRNA-133 (miR-133) is detected by real-time polymerase chain reaction. Tm treatment significantly triggers the apoptosis and ERS of cardiomyocytes. TSA dramatically ameliorates apoptosis and ERS of cardiomyocytes induced by Tm. Interestingly, level of miR-133 is reduced by Tm treatment, which is reversed by TSA. The cardioprotective effect of TSA on apoptosis and ERS of cardiomyocytes is blocked by anti-miR-133. These results suggest that TSA protects cardiomyocytes through ameliorated ERS-mediated apoptosis, which may be resulted from upregulation of miR-133.

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“…To cope with ER stress, eukaryotic cells activate the unfolded protein response to facilitate cancer proliferation by increasing levels of ER protein-folding enzymes and chaperones, enhancing the degradation of misfolded proteins, and reducing protein translation, thus targeting these ER hosted dynamic signaling network can lead increase or decrease of ROS levels in cancer cells and thereby influence overall cell fate [27]. These ER targets include inositol-requiring enzyme-1, protein kinase R-like endoplasmic reticulum kinase, and activating transcription factor-6 [26], glucose-regulated proteins [28] [29], heat shock proteins [29]- [31], endoplasmic reticulum disulfide oxidase [32] [33], peroxiredxins and glutathione peroxidases [34]. Efforts to develop small-molecule inhibitors, or monoclonal antibody/non-antibody proteins/vaccines targeting to these targets are underway, several of which have shown high potency and as well as selectivity in preclinical or clinical trials [27] [35].…”

Section: Anticancer Drugs Developed From Targeting Redox Balance Of Cmentioning

confidence: 99%

“…The one is to target the function of endoplasmic reticulum (ER) where eukaryotic cells fold and assemble membrane and secreted proteins before delivery to other cellular compartments or the extracellular environment [24]- [26]. Correctly folded proteins are released from the ER, and poorly folded proteins are retained until they achieve stable conformations; irreparably misfolded proteins are targeted for degradation.…”

Section: Anticancer Drugs Developed From Targeting Redox Balance Of Cmentioning

confidence: 99%

Overview of Research and Development for Anticancer Drugs

Xu¹,

Mao²

2016

JCT

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Anticancer drugs research and development have been the largest market area in the pharmaceutical industry in terms of the number of project, clinical trials and spending. In the last 10 -30 years, targeting therapy for cancers has been developed and achieved enormous clinical effectiveness by transforming some previously deadly malignancies into chronically manageable conditions, but cure problem still remains. This mini review outlined the current status of anticancer drugs development and hinted the opinions of how to further increase the accuracy and efficacy of discovery for cancer treatment.

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Multiple Mechanisms of Unfolded Protein Response–Induced Cell Death

Cited by 160 publications

References 87 publications

Oxidised protein metabolism: recent insights

Oxidised protein metabolism: recent insights

Tanshinone IIA ameliorates apoptosis of cardiomyocytes induced by endoplasmic reticulum stress

Overview of Research and Development for Anticancer Drugs

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