Regulation of constitutive and inducible AHR signaling : complex interactions involving the AHR repressorstar

The AHR is well known for regulating responses to an array of environmental chemicals.A growing body of evidence supports the hypothesis that the AHR also plays perhaps an evenmore important role in modulating critical aspects of cell function including cell growth, death,and migration. As these and other important AHR activities continue to be elucidated, it becomesapparent that attention now must be directed towards the mechanisms through which the AHRitself is regulated. Here, we review what is known of and what biological outcomes have beenattributed to the AHR repressor (AHRR), an evolutionarily conserved bHLH-PAS protein thatinhibits both xenobiotic-induced and constitutively active AHR transcriptional activity inmultiple species. We discuss the structure and evolution of the AHRR and the dominantparadigm of a xenobiotic-inducible negative feedback loop comprised of AHR-mediatedtranscriptional up-regulation of AHRR and the subsequent AHRR-mediated suppression of AHRactivity. We highlight the role of the AHRR in limiting AHR activity in the absence ofxenobiotic AHR ligands and the important contribution of constitutively repressive AHRR tocancer biology. In this context, we also suggest a new hypothesis proposing that, under somecircumstances, constitutively active AHR may repress AHRR transcription, resulting in unbridledAHR activity. We also review the predominant hypotheses on the molecular mechanismsthrough which AHRR inhibits AHR as well as novel mechanisms through which the AHRR mayexert AHR-independent effects. Collectively, this discussion emphasizes the importance of thisunderstudied bHLH-PAS protein in tissue development, normal cell biology, xenobioticresponsiveness, and AHR-regulated malignancy.

Author Posting. © Elsevier B.V., 2009. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Biochemical Pharmacology 77(2009): 485-497, doi:10.1016/j.bcp.2008.09.016.

Supported by P01-ES11624 (D.H.S.), ArtBeCAUSE (D.H.S.), R01ES006272 (M.E.H.),P42ES007381 (M.E.H. and D.H.S.)