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Relationship: 1732

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 General Apoptosis

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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
CYP2E1 activation and formation of protein adducts leading to neurodegeneration adjacent High High Brendan Ferreri-Hanberry (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 Do not cite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

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 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

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
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

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

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

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

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
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

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).