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Relationship: 1866

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Unfolded Prortein Response leads to Apoptosis

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Unfolded Prortein Response

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Apoptosis

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Inhibition of N-linked glycosylation leads to liver injury	adjacent	Not Specified	Not Specified	Arthur Author (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

After UPR activation the downstream target of this pathway, CHOP, triggers apoptosis.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

Hepatocyte apoptosis in response to UPR activation is well documented.Chop is the downstream target that gets activated by the UPR.(Puthalakath et al., 2007) It plays a major role in the induction of cell death (Marciniak et al., 2004)(Liu et al., 2014)

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Chop induces apoptosis through the control of target genes (B’chir et al., 2014);(Teske et al., 2013)

Chop deficiency can reduce the extent of cell death after ER stress (Tamaki et al., 2008)(Hiramatsu et al., 2014)

Forced expression of CHOP increases the induction of cell death (Han et al., 2013) also in hepatocytes. (Uzi et al., 2013)(Rao et al., 2015)(Pfaffenbach et al., no date)

mRNA expression of CHOP can be measured (Kandel-Kfir et al., 2015)

Reviews

(Dara, Ji and Kaplowitz, 2011); (Oyadomari and Mori, 2004); (Urra et al., 2013); (Hetz, 2012); (Sano and Reed, 2013); (Gorman et al., 2012); (Li et al., 2014);

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Due to the complex feedback loops within the UPR it is difficult to make this KER linear. CHOP is also involved in autophagy.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

References

List of the literature that was cited for this KER description. More help

B’chir, W. et al. (2014) ‘Dual role for CHOP in the crosstalk between autophagy and apoptosis to determine cell fate in response to amino acid deprivation’, Cellular Signalling. Elsevier Inc., 26(7), pp. 1385–1391. doi: 10.1016/j.cellsig.2014.03.009.

Dara, L., Ji, C. and Kaplowitz, N. (2011) ‘The contribution of endoplasmic reticulum stress to liver diseases’, Hepatology, 53(5), pp. 1752–1763. doi: 10.1002/hep.24279.

Gorman, A. M. et al. (2012) ‘Stress management at the ER: Regulators of ER stress-induced apoptosis’, Pharmacology and Therapeutics. Elsevier Inc., 134(3), pp. 306–316. doi: 10.1016/j.pharmthera.2012.02.003.

Han, J. et al. (2013) ‘ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death’, Nature Cell Biology. doi: 10.1038/ncb2738.

Hetz, C. (2012) ‘The unfolded protein response: controlling cell fate decisions under ER stress and beyond’, Nature reviews. Molecular cell biology. Nature Publishing Group, 13(2), pp. 89–102. doi: 10.1038/nrm3270.

Hiramatsu, N. et al. (2014) ‘Translational and posttranslational regulation of XIAP by eIF2 and ATF4 promotes ER stress-induced cell death during the unfolded protein response’, Molecular Biology of the Cell, 25(9), pp. 1411–1420. doi: 10.1091/mbc.E13-11-0664.

Kandel-Kfir, M., Almog, T., Shaish, A., Shlomai, G., Anafi, L., Avivi, C., … Kamari, Y. (2015). Interleukin-1α deficiency attenuates endoplasmic reticulum stress-induced liver damage and CHOP expression in mice. Journal of Hepatology. https://doi.org/10.1016/j.jhep.2015.05.012

Li, Y. et al. (2014) ‘New insights into the roles of CHOP-induced apoptosis in ER stress Structure and Properties of C/EBP Homologous Protein Roles of CHOP in ER Stress-Mediated Apoptosis’, Acta Biochim Biophys Sin, 46(8), pp. 629–640. doi: 10.1093/abbs/gmu048.Review.

Liu, K. et al. (2014) ‘CHOP mediates ASPP2-induced autophagic apoptosis in hepatoma cells by releasing beclin-1 from Bcl-2 and inducing nuclear translocation of Bcl-2’, Cell Death and Disease. doi: 10.1038/cddis.2014.276.

Marciniak, S. J. et al. (2004) ‘CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum’, Genes and Development, 18(24), pp. 3066–3077. doi: 10.1101/gad.1250704.

Ohoka, N. et al. (2005) ‘TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death’, EMBO Journal, 24(6), pp. 1243–1255. doi: 10.1038/sj.emboj.7600596.

Oyadomari, S. and Mori, M. (2004) ‘Roles of CHOP/GADD153 in endoplasmic reticulum stress.’, Cell death and differentiation, 11(4), pp. 381–389. doi: 10.1038/sj.cdd.4401373.

Pfaffenbach, K. T. et al. (2010) ‘Linking endoplasmic reticulum stress to cell death in hepatocytes : roles of C / EBP homologous protein and chemical chaperones in palmitate-mediated cell death’, Am J Physiol Endocrinol Metab, 298, pp. 1027–1035. doi: 10.1152/ajpendo.00642.2009.

Pfaffenbach, K. T. et al. (no date) ‘Linking endoplasmic reticulum stress to cell death in hepatocytes: roles of C/EBP homologous protein and chemical chaperones in palmitate-mediated cell death’.

Puthalakath, H. et al. (2007) ‘ER Stress Triggers Apoptosis by Activating BH3-Only Protein Bim’, Cell. doi: 10.1016/j.cell.2007.04.027.

Rao, J. et al. (2015) ‘C/EBP homologous protein (CHOP) contributes to hepatocyte death via the promotion of ERO1α signalling in acute liver failure’, Biochem. J, 466, pp. 369–378. doi: 10.1042/BJ20140412.

Sano, R. and Reed, J. C. (2013) ‘ER stress-induced cell death mechanisms’, Biochimica et Biophysica Acta - Molecular Cell Research. Elsevier B.V., 1833(12), pp. 3460–3470. doi: 10.1016/j.bbamcr.2013.06.028.

Tamaki, N. et al. (2008) ‘CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury.’, American journal of physiology. Gastrointestinal and liver physiology, 294(2), pp. G498-505. doi: 10.1152/ajpgi.00482.2007.

Teske, B. F. et al. (2013) ‘CHOP induces activating transcription factor 5 (ATF5) to trigger apoptosis in response to perturbations in protein homeostasis’, Molecular Biology of the Cell. doi: 10.1091/mbc.E13-01-0067.

Urra, H. et al. (2013) ‘When ER stress reaches a dead end’, Biochimica et Biophysica Acta - Molecular Cell Research. Elsevier B.V., 1833(12), pp. 3507–3517. doi: 10.1016/j.bbamcr.2013.07.024.

Uzi, D. et al. (2013) ‘CHOP is a critical regulator of acetaminophen-induced hepatotoxicity’, Journal of Hepatology. European Association for the Study of the Liver, 59(3), pp. 495–503. doi: 10.1016/j.jhep.2013.04.024.

Yi, L. et al. (2014) ‘Quercetin enhances apoptotic effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in ovarian cancer cells through reactive oxygen species (ROS) mediated CCAAT enhancer-binding protein homologous protein (CHOP)-death receptor 5 pathway’, Cancer Science, 105(5), pp. 520–527. doi: 10.1111/cas.12395.

Zhang, J. et al. (2015) ‘Hepatocyte autophagy is linked to C/EBP-homologous protein, Bcl2-interacting mediator of cell death, and BH3-interacting domain death agonist gene expression’, Journal of Surgical Research. Elsevier Inc, 195(2), pp. 588–595. doi: 10.1016/j.jss.2015.01.039.