|
|
|
|
|
Bradfield, Christopher A.
 Christopher A. Bradfield, PhD
Director, METC
Professor
Research Area: Signal Transduction of PAS Proteins. Mechanisms of environmental sensing, e.g., pollution, hypoxia and light. Application of mouse and yeast genetics to understand toxicant signal transduction pathways. Toxicology of dioxins, PCBs and PAHs by Ah receptor and ARNT. Regulation of xenobiotic metabolism. Developmental toxicology.
Home Dept: Oncology
Affiliated Depts: Molecular and Environmental Toxicology; Genetics
Address
McArdle Laboratory for Cancer Research
School of Medicine and Public Health
1400 University Avenue
Madison, WI 53706
608/262-2024 - Email
Milestones
2002-MERIT R37 - Understanding the significance and role of the family of transcriptional regulators known as PAS proteins, which control a number of processes including xenobiotic metabolism, circadian rhythms, angiogenesis, and neurogenesis
Patents
1992 - Assay for dioxins
1997 - Biological assay for detecting agonists to the Ah receptor
Research
Our laboratory is interested in the biology of environmental sensing. We currently focus on a family of transcriptional regulators known as PAS proteins. Members of this emerging family of proteins control a number of processes, including xenobiotic metabolism (Ah-receptor and ARNT), circadian rhythms (MOP3, MOP4, CLOCK and PER), hypoxia signaling and angiogenesis (HIF1a, HIF2a, HIF3a, ARNT, ARNT2 and MOP3), and neurogenesis (SIM1 and SIM2).
One model system that is currently emphasized is the signal transduction pathway mediated by Ah-receptor/Arnt heterodimeric complex. These helix-loop-helix-PAS proteins regulate the induction of a number of xenobiotic metabolizing enzymes that occur in response to exposure to a variety of polycyclic aromatic environmental pollutants. In addition, the Ah-receptor mediates a second battery of genes responsible for a number of "toxic effects" of dioxins, such as epithelial hyperplasia, immunosuppression, teratogenesis, and tumor promotion.
To understand these proteins and their signal transduction pathways, we take advantage of genetically manipulable organisms such as mice and yeast. We use yeast genetics as a method to identify genes that are required for signaling. The yeast system is particularly valuable in modifier screens to identify novel components of the PAS signaling pathways. Experiments in the murine system help us to understand the physiological function of these proteins. Current areas of interest include the use of gene-targeting to generate informative bHLH-PAS loci and the use of more classical transgenic approaches to construct murine models that will help us characterize the mechanisms that underlie the toxicological and developmental effects of halogenated aromatics like dioxin.
Publications- Bunger MK, Glover E, Moran SM, Walisser JA, Lahvis GP, Hsu EL, Bradfield CA. Abnormal Liver Development and Resistance to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Toxicity in Mice Carrying a Mutation in the DNA Binding Domain of the Aryl Hydrocarbon Receptor. Toxicol Sci. 2008 Jul 27. [Epub ahead of print]
- Lin BC, Sullivan R, Lee Y, Moran S, Glover E, Bradfield CA. Deletion of the aryl hydrocarbon receptor associated protein 9 leads to cardiac malformation and embryonic lethality. J Biol Chem. 2007 Oct 4; [Epub ahead of print]
- McMillan BJ, Bradfield CA. The aryl hydrocarbon receptor sans xenobiotics: endogenous function in genetic model systems. Mol Pharmacol. 2007 72(3):487-98.
- McMillan BJ, McMillan SN, Glover E, Bradfield CA. 2,3,7,8-Tetrachlorodibenzo-p-dioxin induces premature activation of the KLF2 regulon during thymocyte development. J Biol Chem. 2007 282(17):12590-7.
- McMillan BJ, Bradfield CA. The aryl hydrocarbon receptor is activated by modified low-density lipoprotein. Proc Natl Acad Sci U S A. 2007 104(4):1412-7.
- McDearmon EL, Patel KN, Ko CH, Walisser JA, Schook AC, Chong JL, Wilsbacher LD, Song EJ, Hong HK, Bradfield CA, Takahashi JS. Dissecting the functions of the mammalian clock protein BMAL1 by tissue-specific rescue in mice. Science. 2006 314(5803):1304-8.
- Walisser JA, Bradfield CA. A time to divide: does the circadian clock control cell cycle? Dev Cell. 2006 10(5):539-40.
- Dunham EE, Stevens EA, Glover E, Bradfield CA. The aryl hydrocarbon receptor signaling pathway is modified through interactions with a Kelch protein. Mol Pharmacol. 2006 70(1):8-15.
- Harstad EB, Guite CA, Thomae TL, Bradfield CA. Liver deformation in Ahr-null mice: evidence for aberrant hepatic perfusion in early development. Mol Pharmacol. 2006 69(5):1534-41.
- Thomae TL, Stevens EA, Liss AL, Drinkwater NR, Bradfield CA. The teratogenic sensitivity to 2,3,7,8-tetrachlorodibenzo-p-dioxin is modified by a locus on mouse chromosome 3. Mol Pharmacol. 2006 69(3):770-5.
- Jacqueline A. Walisser, Edward Glover, Kalyan Pande, Adam L. Liss, and Christopher A. Bradfield Aryl Hydrocarbon Receptor-dependent Liver Development and Hepatotoxicity Are Mediated by Different Cell Types Proc Natl Acad Sci USA 2005, 102: 17858-17863
- Kevin R. Hayes, Aaron L. Vollrath, Gina M. Zastrow, Brian J. McMillan, Mark Craven, Stevan Jovanovich, David R. Rank, Sharon Penn, Jacqueline A. Walisser, Janardan K. Reddy, Russell S. Thomas, and Christopher A. Bradfield EDGE: A Centralized Resource for the Comparison, Analysis, and Distribution of Toxicogenomic Information
Mol Pharmacol 2005, 67: 1360-1368 - Kevin R. Hayes and Christopher A. Bradfield Advances in Toxicogenomics Chemical Research in Toxicology, 2005, 18: 403-414.
- Maureen K. Bunger, Lisa D. Wilsbacher, Susan M. Moran, Cynthia Clendenin, Laurel A. Radcliffe, John B. Hogenesch, M. Celeste Simon, Joseph S. Takahashi, and Christopher A. Bradfield Mop3 Is an Essential Component of the Master Circadian Pacemaker in Mammals. C Cell 2000, 103: 1009–1017.
- Maltepe, E., Schmidt, J.V., Baunoch, D., Bradfield, C.A., and Simon, M.C. 1997. Arnt is essential for responses to oxygen, glucose deprivation and developmental angiogenesis in the mouse. Nature. 386:403-40.
Check PubMed for other publications by Christopher A. Bradfield
|
|
