Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|IKK complex inhibition leading to liver injury||MolecularInitiatingEvent|
Key Event Description
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)
- Adenosine triphosphate (ATP) analogues (e.g. beta-carboline, SC-839): specific IKK interaction, preference for IKK subunits(Kishore et al. 2003)
- Allosteric effect on IKK complex (Burke et al. 2003)
- 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
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
Evidence for Perturbation by Stressor
Overview for Molecular Initiating Event
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.