API

Relationship: 1732

Title

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Unfolded Prortein Response leads to General Apoptosis

Upstream event

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Unfolded Prortein Response

Downstream event

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General Apoptosis

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
CYP2E1 activation and formation of protein adducts leading to neurodegeneration adjacent High High

Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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During the UPR several proteins are released from the ER. When cells have too much stress, due to ROS or other factors, and can’t restore the ER homeostasis pro-death programs are activated. This is done by the proteins IRE1, PERK and ATF-6 which are released from the ER. The main protein involved in apoptosis is CHOP, which is part of the pathway after activation of the PERK protein. But also IRE1 plays a big role in the cell death regulation.

Evidence Supporting this KER

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Several studies are performed using western blotting and inhibition assays to find out which proteins are activated in UPR and which have a role in cell death. CHOP has two different roles, which can induce cell death or has a protective function for survival. CHOP is activated by ATF4, which is first activated by a phosphorylated eIF2a. eIF2a is phosphorylated by an activated PERK. IRE1 and PERK activation leads to higher expression of caspases which induce cell death, by Nf-kB and ATF4 activation respectively. Another study showed a direct link between UPR and apoptosis. DHCR24 inhibited apoptosis by interfering with ER stress which resulted in lower levels of CHOP.

Biological Plausibility

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That UPR can induce apoptosis is known, but the exact mechanism is not completely clear since many proteins play a role.

Empirical Evidence

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Uncertainties and Inconsistencies

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Different forms of ER stress can lead to different UPR reactions.

Quantitative Understanding of the Linkage

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Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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References

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Foufelle, F. & Fromenty, B. Role of endoplasmic reticulum stress in drug-induced toxicity. Pharmacol. Res. Perspect. 4, e00211 (2016).

Hiramatsu, N., Chiang, W. C., Kurt, T. D., Sigurdson, C. J. & Lin, J. H. Multiple Mechanisms of Unfolded Protein Response-Induced Cell Death. Am. J. Pathol. 185, 1800–1808 (2015).

Sano, R. & Reed, J. C. ER stress-induced cell death mechanisms. Biochimica et Biophysica Acta - Molecular Cell Research 1833, 3460–3470 (2013).

Hiramatsu, N. et al. Translational and posttranslational regulation of XIAP by eIF2  and ATF4 promotes ER stress-induced cell death during the unfolded protein response. Mol. Biol. Cell 25, 1411–1420 (2014).

Shah, A. & Kumar, A. Methamphetamine-mediated endoplasmic reticulum (ER) stress induces type-1 programmed cell death in astrocytes via ATF6, IRE1 beta and PERK pathways. Oncotarget 7, 46100–46119 (2016).

Han, J. et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat. Cell Biol. 15, 481–490 (2013).

Lu, X. et al. 3 ??-hydroxysteroid-?? 24 reductase (DHCR24) protects neuronal cells from apoptotic cell death induced by Endoplasmic Reticulum (ER) stress. PLoS One 9, (2014).