PT  - JOURNAL ARTICLE
AU  - Dunham, Elizabeth E.
AU  - Stevens, Emily A.
AU  - Glover, Edward
AU  - Bradfield, Christopher A.
TI  - The Aryl Hydrocarbon Receptor Signaling Pathway Is Modified through Interactions with a Kelch Protein
AID  - 10.1124/mol.106.024380
DP  - 2006 Jul 01
TA  - Molecular Pharmacology
PG  - 8--15
VI  - 70
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/70/1/8.short
4100  - http://molpharm.aspetjournals.org/content/70/1/8.full
SO  - Mol Pharmacol2006 Jul 01; 70
AB  - The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor with important roles in metabolic adaptation, dioxin toxicology, and vascular development. To understand the details of this signal transduction pathway, we have used the yeast two-hybrid system to identify proteins that physically interact with the AHR in a ligand-dependent manner. Using this strategy, we identified a novel modifier of the AHR signaling pathway that we named Ah-receptor associated protein 3 (ARA3). Coexpression of ARA3 with an AHR chimera in yeast and mammalian cells enhances signaling in response to agonists. The human full-length cDNA previously was described as influenza virus nonstructural protein-1 binding protein (NS1BP). This protein contains four apparent domains—a “broad complex/tramtrack/bric-a-brac” (BTB) domain, a “kelch” domain, a “BTB and C-terminal kelch” (BACK) domain, and an intervening region (IVR). The carboxyl terminus of the AHR “Per-ARNT-Sim” (periodicity/AHR nuclear translocator/simple-minded) domain and the BACK/IVR domains of ARA3 mediate the AHR-ARA3 interaction. The BACK/IVR domains of ARA3 also are sufficient to modify AHR signaling in yeast and mammalian cells. In an effort to provide a preliminary model of NS1BP activity in AHR signaling, we demonstrate that NS1BP regulates the concentration of functional AHR in mammalian cells.