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Event: 1574

Key Event Title

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

Inhibition, IKK complex

Short name
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Inhibition, IKK complex
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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

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

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 MolecularInitiatingEvent Nanette Vrijenhoek (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

The IKK complex consists of 3 subunits: IKKa, IKKb and NEMO. Normally, this complex can activate NFkB signaling. However, in this MIE, this complex will be disturbed in such a way it can not perform that function anymore. Currently, 3 types of IKK disturbances have been described: (Gupta et al. 2010)

  1. Adenosine triphosphate (ATP) analogues (e.g. beta-carboline, SC-839): specific IKK interaction, preference for IKK subunits(Kishore et al. 2003)
  2. Allosteric effect on IKK complex (Burke et al. 2003)
  3. Interaction with Cys-179 in activation loop of IKKb
  • List of Cys-179 interacting compounds: (Heyninck et al. 2014)

However, not many studies performed tests on compounds of interest to identify the specific mechanisms of IKK complex inhibition (Gupta et al. 2010).

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

Interaction compound-IKK complex: Western blot with IKK antibodies in purified IKK complexes (Heyninck et al. 2014).

IKK activity: In vitro IKK kinase assay (CycLex IKKb inhibitor screening kit) (Heyninck et al. 2014).

Specific Cys-179 interaction: Mutant IKKb treatment followed by Western blotting with antiFLAG (Heyninck et al. 2014).

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

Burke, J.R. et al., 2003. BMS-345541 is a highly selective inhibitor of I??B kinase that binds at an allosteric site of the enzyme and blocks NF-??B-dependent transcription in mice. Journal of Biological Chemistry, 278(3), pp.1450–1456.

Gupta, S.C. et al., 2010. Inhibiting NF-??B activation by small molecules as a therapeutic strategy. Biochimica et Biophysica Acta - Gene Regulatory Mechanisms, 1799(10–12), pp.775–787. Available at: http://dx.doi.org/10.1016/j.bbagrm.2010.05.004.

Heyninck, K. et al., 2014. Withaferin A inhibits NF-kappaB activation by targeting cysteine 179 in IKKβ. Biochemical Pharmacology, 91(4), pp.501–509. Available at: http://dx.doi.org/10.1016/j.bcp.2014.08.004.

Kishore, N. et al., 2003. A selective IKK-2 inhibitor blocks NF-κB-dependent gene expression in interleukin-1β-stimulated synovial fibroblasts. Journal of Biological Chemistry, 278(35), pp.32861–32871.

Zhou, P. et al., 2010. Flavokawain B, the hepatotoxic constituent from kava root, induces GSH-sensitive oxidative stress through modulation of IKK/NF- B and MAPK signaling pathways. The FASEB Journal, 24(12), pp.4722–4732. Available at: http://www.fasebj.org/cgi/doi/10.1096/fj.10-163311.