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Event: 1575

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Activation, Caspase 8 pathway

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
IKK complex inhibition leading to liver injury	KeyEvent	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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

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

Sex Applicability

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

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

In the caspase 8 pathway, the TRADD adaptor protein recruits FADD after TNFa stimulus and forms a complex together with pro-caspase 8. Caspase 8 will be activated and can directly activate caspase-3 which leads to apoptosis (Melino & Vaux 2010). Furthermore, Caspase 8 can also splice Bid to tBid which promotes disruption of the membrane of mitochondria. Cytochrome C will be released and activate Caspase 9 and Apaf1, which in turn stimulate caspase 8, causing apoptosis (Frederiksson 2012).(Cullen & Martin 2009)

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

WesternBlot (pro) caspase 8 (Fotin-Mleczek et al. 2002)(Schattenberg et al. 2011)

Caspase 8 specific fluorogenic substrates(Schattenberg et al. 2011)

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

References

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

Melino, G. & Vaux, D., 2010. Cell Death G. Melino & D. Vaux, eds.,

Frederiksson, L., 2012. TNFalpha-signaling in drug induced liver injury. University of Leiden.

Cullen, S.P. & Martin, S.J., 2009. Caspase activation pathways: Some recent progress. Cell Death and Differentiation, 16(7), pp.935–938. Available at: http://dx.doi.org/10.1038/cdd.2009.59.

Fotin-Mleczek, M. et al., 2002. Apoptotic crosstalk of TNF receptors: TNF-R2-induces depletion of TRAF2 and IAP proteins and accelerates TNF-R1-dependent activation of caspase-8. Journal of cell science, 115(Pt 13), pp.2757–2770.

Schattenberg, J.M. et al., 2011. Ablation of c-FLIP in hepatocytes enhances death-receptor mediated apoptosis and toxic liver injury in vivo. Journal of Hepatology, 55(6), pp.1272–1280. Available at: http://dx.doi.org/10.1016/j.jhep.2011.03.008.