Key Event Title
|Level of Biological Organization|
Key Event Components
|signaling||nuclear receptor subfamily 1 group I member 3||increased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|CAR activation- Hepatocellular tumors||MolecularInitiatingEvent|
Key Event Description
The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor that is expressed primarily in the liver, which can be activated by xenobiotics or by certain endogenous cellular metabolites. CAR normally is tethered in the cytoplasm of a hepatocyte via a set of specific proteins including heat shock protein 90 (HSP90) and other chaperones. Chemical ligands bind to the ligand binding site of CAR, and a conformational change frees CAR from the tethering proteins and facilitates its transport into the nucleus. In addition, indirect CAR activators (e.g. phenobarbital) can bind to the EGF receptor to initiate a series of steps that eventually dephosphorylate a critical Threonine-38 residue in CAR, allowing it to migrate into the nucleus. Inside the nucleus, CAR dimerizes with RXR and this CAR-RXR complex binds to specific response elements on the DNA to activate transcription of specific CAR-responsive genes. CAR is unique among nuclear receptors, in that it is constitutively active when in the nucleus, i.e. it will spontaneously dimerize with RXR and alter gene expression, even without an activator bound to its ligand binding domain. When activated and translocated to the nucleus, CAR alters the transcription of multiple genes, which can be characterized as falling into three general areas of biological function: 1) Phase I and II metabolizing enzymes plus transporters; 2) decreases in lipogenesis and gluconeogenesis enzymes; and 3) species-specific alteration of cell proliferation and apoptosis signals.
In terms of this AOP, CAR activation in rat or mouse hepatocytes directly leads to altered expression of genes that produce an intracellular signal for increased cell proliferation.
How It Is Measured or Detected
Domain of Applicability
Evidence for Perturbation by Stressor
Overview for Molecular Initiating Event