Mammalian Per-Arnt-Sim Proteins in Environmental Adaptation Brian E. McIntosh, 1 John B. Hogenesch, 2 and Christopher A. Bradfield 1 1 McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin 53706; email: bemcintosh@wisc.edu, bradfield@oncology.wisc.edu 2 Department of Pharmacology, Institute for Translational Medicine and Therapeutics, Penn Genome Frontiers Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; email: hogenesc@mail.med.upenn.edu Annu. Rev. Physiol. 2010. 72:625–45 First published online as a Review in Advance on November 13, 2009 The Annual Review of Physiology is online at physiol.annualreviews.org This article’s doi: 10.1146/annurev-physiol-021909-135922 Copyright c  2010 by Annual Reviews. All rights reserved 0066-4278/10/0315-0625$20.00 Key Words dioxin, hypoxia, toxicology, circadian, genetics, mouse, channel Abstract The Per-Arnt-Sim (PAS) domain is conserved across the kingdoms of life and found in an ever-growing list of proteins. This domain can bind to and sense endogenous or xenobiotic small molecules such as molecular oxygen, cellular metabolites, or polyaromatic hydrocarbons. Members of this family are often found in pathways that regulate re- sponses to environmental change; in mammals these include the hy- poxia, circadian, and dioxin response pathways. These pathways func- tion in development and throughout life to regulate cellular, organ, and whole-organism adaptive responses. Remarkably, in the case of the clock, this adaptation includes anticipation of environmental change. In this review, we summarize the roles of PAS domain–containing proteins in mammals. We provide structural evidence that functionally classifies both known and unknown biological roles. Finally, we discuss the role of PAS proteins in anticipation of and adaptation to environmental change. 625 Annu. Rev. Physiol. 2010.72:625-645. Downloaded from arjournals.annualreviews.org by University of Wisconsin - Madison on 02/14/10. For personal use only.