RT Journal Article
SR Electronic
T1 The Aryl Hydrocarbon Receptor Signaling Pathway Is Modified through Interactions with a Kelch Protein
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 8
OP 15
DO 10.1124/mol.106.024380
VO 70
IS 1
A1 Dunham, Elizabeth E.
A1 Stevens, Emily A.
A1 Glover, Edward
A1 Bradfield, Christopher A.
YR 2006
UL http://molpharm.aspetjournals.org/content/70/1/8.abstract
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.