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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.

Pubmed ID: 16582008

Authors

  • Dunham EE
  • Stevens EA
  • Glover E
  • Bradfield CA

Journal

Molecular pharmacology

Publication Data

July 22, 2006

Associated Grants

  • Agency: NCI NIH HHS, Id: P30-CA014520
  • Agency: NIEHS NIH HHS, Id: R01 ES005703
  • Agency: NIEHS NIH HHS, Id: R01 ES006883
  • Agency: NIEHS NIH HHS, Id: R37-ES005703
  • Agency: NCI NIH HHS, Id: T32-CA009135

Mesh Terms

  • Animals
  • Binding Sites
  • COS Cells
  • Carrier Proteins
  • Cercopithecus aethiops
  • Humans
  • Mutation
  • Nuclear Proteins
  • Plasmids
  • Protein Binding
  • Receptors, Aryl Hydrocarbon
  • Signal Transduction
  • Transcription Factors
  • Two-Hybrid System Techniques