Received for publication March 17, 2006.
Revised March 30, 2006.
Accepted for publication March 31, 2006.

The Aryl Hydrocarbon Receptor Signaling Pathway is Modified through Interactions with a Kelch Protein

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor with important roles in metabolic adaptation, dioxin toxicology and vascular development. In order 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, which 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 and bric a` brac" (BTB) domain, a "kelch" domain, a "BTB and C-terminal kelch" (BACK) domain, and an intervening region (IVR). The carboxy-terminus of AHR's "Per-ARNT-Sim" (PAS) 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.

Key words: Yeast 2-hybrid, Ah receptor

This article has been cited by other articles:

				A. B. Okey An Aryl Hydrocarbon Receptor Odyssey to the Shores of Toxicology: The Deichmann Lecture, International Congress of Toxicology-XI Toxicol. Sci., July 1, 2007; 98(1): 5 - 38. [Abstract] [Full Text] [PDF]