Negishi, Masahiko (NIEHS)
CAR (nuclear constitutive active receptor) is a member of the nuclear receptor superfamily, and is a key regulator of xenobiotic and endobiotic metabolism. It is primarily responsible for sensing foreign toxic substances and in response up regulating the expression of proteins involved in the detoxification and clearance of these substances from the body. CAR is constitutively active in the absence of a ligand but is regulated by both agonists and inverse agonists. The ligand binding results in the translocation of this protein to the nucleus, where it activates or represses target gene transcription. These ligands include bilirubin, a variety of foreign compounds, steroid hormones, and prescription drugs. Although the nuclear orphan constitutive active receptor (CAR) has been identified as a key transcription factor that regulates the induction of CYP2B, the full scope of CAR-regulated genes still remains a major question. To understand the molecular and cellular mechanisms of these complex processes and enable prediction/prevention nuclear receptor-mediated diseases after environmental exposures, the NIEHS inventors generated a mouse strain that has lost the constitutive CAR function. The CAR KO mouse can be used to investigate CAR-regulated genes and cellular mechanisms.
- The CAR KO mouse can be used to investigate CAR-regulated genes and cellular mechanisms. Once CAR-mediated pathways of tumor promotion are defined at the molecular level, the receptor can be useful as a drug target for hepatocellular carcinoma prevention.