Ph.D., Food Toxicology, Oregon State University

M.S., Food Science, University of Maryland

B.S., Food Science, University of Maryland

Molecular mechanism(s) of toxicity, dioxin-mediated signal transduction, regulation of cellular homeostasis by the Ah receptor, Ah receptor-mediated control of gene expression; biochemistry of heat shock protein complexes

Ah receptor-mediated toxicity

We are interested in the long-term health effects of persistent exposure to industrial pollutants. Dioxin and other halogenated polycyclic aromatic hydrocarbons (HPAHs) are produced during the combustion of organic matter and as a result of bleaching paper. The Ah receptor plays a central role in the biological response to dioxin, which is both carcinogenic and toxic. The Ah receptor is a member of a family of helix-loop- helix/basic region transcriptional factors. Upon binding a HPAH, the Ah receptor translocates to the nucleus and heterodimerizes with Arnt, another helix-loop-helix/basic region protein. This heterodimer is subsequently able to bind to a specific enhancer core sequence in the nucleus, leading to alter transcription of a set of genes. This sequence of events is believed to result in the high level of toxicity observed with many HPAHs and perhaps the tumor-promoting properties of dioxins. We are examining a number of biochemical properties of the Ah receptor, including the level of receptor heterogeneity, composition of the inactive form of the receptor, proteolytic turnover of liganded receptor, and its ability to interact with other transcription factors. We are testing whether structurally diverse Ah receptor ligands can illicit differing gene expression patterns. Ligand-independent function of the Ah receptor in normal cellular processes is also being explored, using a variety of molecular techniques. The critical target genes regulated by the Ah receptor that lead to toxicity are being identified through DNA microarray analysis. Through this series of studies, we hope to gain an understanding of the multiple points of regulation of the Ah receptor and its role in dioxin-mediated toxicity and normal cell biology. Yet another issue that we are addressing is whether the human Ah receptor can mediate toxicity of dioxin in a transgenic mouse model.

Role of the Ah receptor in physiology

The Ah receptor plays an important role in normal cellular physiology; this is best exemplified by the phenotype in mice where the Ah receptor gene has been disrupted. Ah receptor null mice exhibit a number of defects, such as; low productive success, abnormal vasculature in the liver, small liver size and altered immune system. We are interested in how the activity of the Ah receptor is regulated under normal physiologic conditions; this is being explored by screening certain endogenous chemicals for their ability to activate the Ah receptor. A number of nuclear receptors (e.g. estrogen receptor) have been shown to modulate transcriptional activity through tethering to other transcription factors at the promoter region of genes. We have developed a point mutant of the Ah receptor that fails to bind to DNA, yet stills binds ligand and heterodimerizes with ARNT. A transgenic mouse has been developed that expresses this mutant receptor and the transgene has been crossed onto an Ah receptor null background. DNA microarray studies have been performed to determine whether the Ah receptor can regulate gene expression through protein-protein interactions. A number of biochemical pathways important in human health are attenuated by activation of the Ah receptor. Ah receptor ligands that can selectively elicit a transrepression response, and not a DNA binding response (e.g. induction of CYP1A1), are currently being designed and screened. Studies are being designed to examine whether the Ah receptor will be an important drug target.

Lab members:

Chris Chairo- Genetics Graduate program
Luis Morales- Biochemistry Graduate program
Brett DiNatale- Molecular Medicine Graduate program
Colin Flaveny- Toxicology Graduate program
Rushang Patel- Molecular Medicine Graduate program
Ann Kusnadi- Research Associate
Iain Murray - Postdoctoral Fellow
Jennifer Schroeder- Postdoctoral Fellow
Kelly Wagner- Technician

Lab Alumni (partial list):

Hollie Swanson- Associate Professor- University of Kentucky
Murray Whitelaw- Associate Professor- University of Adelaide
Norman Nord- Associate Professor- Michigan State University
Steve Levine- Scientist- Monstanto
David Carlson- FDA, drug approval division
Brian Meyer- Scientist- Merck Laboratories
Mohan Kumar - Scientist- RheoGene, Inc.
Peter Long- Patent Attorney
John Petrulis- Scientist- Schering-Plough
Preeti Ramadoss - Post-doctoral fellow Harvard
Brett Hollingshead - Post-doctoral fellow- National Cancer Institute

Chiaro, C.C., Patel, R.D., Marcus, C.B., and Perdew, G.H. (2007) Evidence for an Ah receptor-mediated cytochrome P450 auto-regulatory pathway. Mol. Pharmacol. Epub.

Sun, Y.-W., Herzog, C., Krzeminski, J., Amin, S., Perdew, G.H., and El-Bayoumy, K. (2007) Effects of the environmental mammary carcinogen 6-nitrochrysene on p53 and p21 Cip1 protein expression and cell cycle regulation in MCF-7 and MCF-10A cells. Chem. Biol. Interaction. In press.

Patel, R.D., Hollingshead, B.D., Omiecinski, C., and Perdew, G.H. (2007) Aryl-hydrocarbon receptor activation regulates constitutive androstane receptor (CAR) levels in murine and human liver. Hepatology, 46 , 209-218.

Morales, J.L., and Perdew, G.H. (2007) CHIP can remodel mature AhR complexes and mediate ubiquitination of both AhR and the hsp90 in vitro. Biochemistry. 46 , 610-621.

Hollingshead, B.D., Patel, R.D., and Perdew, G.H. (2006) Endogenous hepatic expression of the hepatitis B virus X-associated protein 2 is adequate for maximal association with aryl hydrocarbon receptor-hsp90 complexes. Mol. Pharmacol. 70 , 2096-2107.

Chen, Y-H., Beischlag, T.V., Kim, J.H., Perdew, G.H., and Stallcup, M.R. (2006) Role of GAC63 in transcriptional activation by the aryl hydrocarbon receptor. J. Biol. Chem. 281 , 12242-12247.

Patel, R.D., Kim, D.J., Peters, J.M., and Perdew, G.H. (2006) The aryl hydrocarbon receptor directly regulates expression of the potent mitogen epiregulin. Toxicological Sciences 89 , 75-82.

Murray, I.A., Reen, R.K., Leathery, N., Ramadoss, P., Bonati, L., Gonzalez, F.J., Peters, J.M., and Perdew G.H. (2005) Evidence that ligand binding is a key determinant of Ah receptor-mediated transcriptional activity . Arch. Biochem. Biophys. 442 , 59-71.

Ramadoss, P., and Perdew, G.H. (2005) The transactivation domain of the Ah receptor is a key determinant of cellular localization and ligand-independent nucleo-cytoplasmic shuttling properties. Biochemistry 44 , 11148-59.

Beischlag, T.V. and Perdew, G.H. (2005) ER a -AhR-ARNT protein-protein interactions mediate estradiol-dependent transrepression of dioxin inducible gene transcription. J. Biol. Chem. 280 , 21607-21611.

Ramadoss, P., Marcus, C., and Perdew, G.H. (2005) Role of the Ah receptor in drug metabolism. Expert Opin. Drug Metab. Toxicol. 1 , 9-21.

Gray, J.P., Burns, K.A., Leas, T.L., Perdew, G.H., and Vanden Heuvel, J.P. (2005) Regulation of Peroxisome Proliferator-Activated Receptor alpha by Protein Kinase C. Biochemistry 44 , 10313-21.

 Kim, D.J., Murray, I.A., Burns, A.M., Gonzalez, F.J., Perdew, G.H., and Peters, J.M. (2005) Peroxisome proliferators-activated receptor- b / d (PPAR b / d ) inhibits epidermal cell proliferation by down-regulation of kinase activity. J. Biol. Chem. 280 , 9519-9527.