The aryl hydrocarbon receptor signaling pathway is modified through interactions with a Kelch protein.
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.
Dunham
Elizabeth E
EE
McArdle Laboratory for Cancer Research, 1400 University Avenue, Madison, WI 53706-1599, USA.
Stevens
Emily A
EA
Glover
Edward
E
Bradfield
Christopher A
CA
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D011485:Protein Binding; D016601:RNA-Binding Proteins; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D002352:Carrier Proteins; C114207:IVNS1ABP protein, human; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors