Christopher A. Bradfield, Ph.D. Professor McArdle Laboratory for Cancer Research bradfield@oncology.wisc.edu Professor Bradfield's Website

Trainer in the Following Programs:
Oncology
Genetics
Cellular and Molecular Biology
Molecular and Cellular Pharmacology

Honors and Awards

Our laboratory is interested in a family of cellular sensor known as PAS proteins. Members of this emerging family of transcriptional regulators control a number of biological processes, including xenobiotic metabolism (Ah-receptor and ARNT), circadian rhythms (MOP3, MOP4 MOP9, CLOCK and PER), angiogenesis (HIF1a, HIF2a, HIF3a, ARNT, ARNT2 and MOP3), and neurogenesis (SIM1 and SIM2). The 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. Most recently we have shown that these proteins also regulate the resolution of fetal vascular structures during mammalian development.

To understand these proteins and their signal transduction pathways, we are focusing on their characterization in genetically manipulable organisms such as mice and yeast. We use yeast genetics as a method to identify genes that are required for signaling. Experiments in the murine system help us to understand the physiological function of these proteins, as well as to identify new members of the PAS superfamily. Current areas of interest include the use of gene targeting to generate informative bHLH-PAS loci and the use of high throughput DNA sequencing and microarray to understand the carcinogenic mechanisms of halogenated aromatics like dioxin.

Selected Publications:

• Walisser JA, Bradfield CA. (2006) A time to divide: does the circadian clock control cell cycle? Dev Cell. 10(5):539-40.
  
  
• Dunham EE, Stevens EA, Glover E, Bradfield CA. (2006) The aryl hydrocarbon receptor signaling pathway is modified through interactions with a Kelch protein. Mol Pharmacol. 70(1):8-15.
  
  
• Harstad EB, Guite CA, Thomae TL, Bradfield CA. (2006) Liver deformation in Ahr-null mice: evidence for aberrant hepatic perfusion in early development. Mol Pharmacol. 69(5):1534-41.
  
  
• Thomae TL, Stevens EA, Liss AL, Drinkwater NR, Bradfield CA. (2006) The teratogenic sensitivity to 2,3,7,8-tetrachlorodibenzo-p-dioxin is modified by a locus on mouse chromosome 3. Mol Pharmacol. 69(3):770-5.
  
  
• Walisser JA, Glover E, Pande K, Liss AL, Bradfield CA. (2006) Aryl hydrocarbon receptor-dependent liver development and hepatotoxicity are mediated by different cell types. Proc Natl Acad Sci U S A. 102(49):17858-63.
  
  
• Hayes KR and Bradfield CA. (2005). Advances in toxicogenomics.  Chem Res Toxicol. 18:403-414.
  
  
• Pande K, Moran SM, and Bradfield CA. (2005). Aspects of dioxin toxicity are mediated by interleukin 1-like cytokines. Mol Pharmacol. 67:1393-1398.
  
  
• Walisser, JA, Bunger, MK, Glover, E, Harstad, EB and Bradfield, CA. (2004). Patent ductus venosus and dioxin resistance in mice harboring a hypomorphic Arnt allele. Journal of Biological Chemistry, 279:16326 -16331.
  
  
• Yao, G, Craven, M, Drinkwater, N and Bradfield, CA. (2004). Interaction networks in yeast define and enumerate the signaling steps of the vertebrate Ah receptor. PLOS Biology. 2:355-367.
  
  
• Bunger, MK, Moran, SM, Glover, E, Thomae, TL, Lahvis, GP, Lin, BC, and Bradfield, CA. (2003). Resistance to 2,3,7,8-tetrachclordibenzo-p-dioxin toxicity and abnormal liver development in mice carrying a mutation in the nuclear localization sequence of the aryl hydrocarbon receptor. Journal of Biological Chemistry, 278:17767 -17774.
  
  
• Bittinger, MA, Nguyen, LP, Bradfield, CA. (2003). Aspartate aminotransferase generates proagonists of the aryl hydrocarbon receptor. Molecular Pharmacology, 64:550-556.
  
  
• Yao, G, Harstad, EB and Bradfield, CA. (2003). The Ah receptor. PAS Proteins: Regulators and Sensors of Development and Physiology, (S. Crews, Ed.). Pages 149-182. Kluwer Academic Publishers, Boston, MA.
  
  
• Thomas, R.S., Rank, D.R., Penn, S.G., Zastrow, G.M., Hayes, K.R., Pande, K., Glover, E., Silander, T., Craven, M.W., Reddy, J.K., Jovanovich, S.B., and Bradfield, C.A. (2001). Identification of toxicologically predictive gene sets using cDNA microarrays. Mol. Pharmacol. 60:1189-1194.
  
  
• Bunger, M.K., Wilsbach, L. D., Moran, S.M., Clendenin, C., Radcliffe, L.A., Hogenesch, J.B., Simon M.C., Takahashi, J.S., Bradfield, C.A. (2000). Mop3 is an essential Component of the Master Circadian Pacemaker in Mammals. Cell 103:1009 -1017 http://www.cell.com/cgi/content/reprint/103/7/1009
  
  
• LaPres, J.J., Edward, G., Dunham, E.E., and Bradfield, C.A. (2000). ARA9 modifies agonist signaling through an increase in available aryl hydrocarbon receptor. J. Biol. Chem. 275:6153-6159.
  
  
• Lahvis, G.P., Lindell, S.L., Thomas, R.S., McCuskey, R.S., Murphy, C., Glover, E., Bentz, M., Southard, J. and Bradfield, C.A.
  (2000). Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice. PNAS 97:10442-10447.
  
  
• Hogenesch, J.B., Gu, Y.Z., Moran, S.M., Shimomura, K., Radcliffe, L.A., Takahashi, J.S., and Bradfield, C.A. (2000). The bHLH-PAS protein MOP9 is a brain specific heterodimeric partner of circadian and hypoxia factors. J. Neurosci 20:RC83, 1-5.
  
  
• Gu, Y.G., Hogenesch, J.B., and Bradfield, C.A. (2000). The PAS superfamily: Sensors of environmental and developmental signals. Annual Reviews of Pharmacology and Toxicology. (K Ramos, et al, eds.). Annual Reviews Inc., Palo Alto, CA. Chapter 22, Pages 519-561.
  
  
• Chan, W.K., Yao, G., Gu, Y.Z., and Bradfield, C.A. (1999). Cross talk between the Aryl hydrocarbon receptor and hypoxia inducible factor signaling pathways: Mechanism of competition and compensation. J. Biol. Chem. 274:12115-12123.
  
  
• Carver, L.A., LaPres, J.J., Jain, S., Dunham, E.E., and Bradfield, C.A. (1998). Characterization of the Ah receptor associated protein, ARA9. J. Biol. Chem. 273:33580-33587.
  
  
• Gu, Y.Z., Moran, S.M., Hogenesch, J.B., Wartman, L. and Bradfield, C.A. (1998). Molecular characterization and chromosomal localization of a third-class hypoxia inducible factor, HIF1. Gene Expression 7:205-213.