The Ah receptor (AhR) has been shown to be responsible for the carcinogenic and toxic properties of 2,3,7,8- tetrachloro-p-dioxin (TCDD) in rodent models. The human population is exposed to low doses of TCDD, and a number of other AhR ligands, the actual health effects of exposure remain to be established. Whether or not data generated in the mouse model can be effectively extrapolated to humans will require a better understanding of potential genetic differences between species. The central hypothesis to be tested is that the human AhR is biochemically different from the mouse AhR and these differences result in altered AhR-mediated activity. An additional goal of the proposed studies is to better understand the multiple mechanisms of regulation of the AhR. The central hypothesis is supported by preliminary findings from our laboratory. In this application the biochemical and transcriptional activity of the human AhR will be characterized and compared with the mouse AhR(s).
Three specific aims are proposed; l) Determine the biochemical behavior of the human vs. mouse Ah receptor in the core unliganded receptor complex, and examine the ability of XAP2 to alter the activity of the human vs. mouse AhR, 2) Examine the transactivation potential, co-activator recruitment specificity and nucleocytoplasmic shuttling properties of the human AhR compared with the mouse AhR through the use of chimeric receptors, and 3) Compare the ability of the liganded human AhR vs. the mouse AhR to alter gene expression in AhR-null tsSV-40 transformed mouse hepatocyte cell lines. In these aims the mouse AhR and human AhR will be studied in the same cell line to allow a direct determination of species differences independent of cell context variation present in previous studies. Collectively, these studies will establish the level of divergence in human vs. mouse AhR function and should allow a better assessment of the significance of human exposure to TCDD. ? ? ?
|Hollingshead, Brett D; Beischlag, Timothy V; Dinatale, Brett C et al. (2008) Inflammatory signaling and aryl hydrocarbon receptor mediate synergistic induction of interleukin 6 in MCF-7 cells. Cancer Res 68:3609-17|
|Flaveny, Colin; Reen, Rashmeet K; Kusnadi, Ann et al. (2008) The mouse and human Ah receptor differ in recognition of LXXLL motifs. Arch Biochem Biophys 471:215-23|
|Morales, Jose Luis; Krzeminski, Jacek; Amin, Shantu et al. (2008) Characterization of the antiallergic drugs 3-[2-(2-phenylethyl) benzoimidazole-4-yl]-3-hydroxypropanoic acid and ethyl 3-hydroxy-3-[2-(2-phenylethyl)benzoimidazol-4-yl]propanoate as full aryl hydrocarbon receptor agonists. Chem Res Toxicol 21:472-82|
|Murray, Iain A; Perdew, Gary H (2008) Omeprazole stimulates the induction of human insulin-like growth factor binding protein-1 through aryl hydrocarbon receptor activation. J Pharmacol Exp Ther 324:1102-10|
|Beischlag, Timothy V; Luis Morales, J; Hollingshead, Brett D et al. (2008) The aryl hydrocarbon receptor complex and the control of gene expression. Crit Rev Eukaryot Gene Expr 18:207-50|
|Morales, J Luis; Perdew, Gary H (2007) Carboxyl terminus of hsc70-interacting protein (CHIP) can remodel mature aryl hydrocarbon receptor (AhR) complexes and mediate ubiquitination of both the AhR and the 90 kDa heat-shock protein (hsp90) in vitro. Biochemistry 46:610-21|
|Chiaro, Christopher R; Patel, Rushang D; Marcus, Craig B et al. (2007) Evidence for an aryl hydrocarbon receptor-mediated cytochrome p450 autoregulatory pathway. Mol Pharmacol 72:1369-79|
|Patel, Rushang D; Hollingshead, Brett D; Omiecinski, Curtis J et al. (2007) Aryl-hydrocarbon receptor activation regulates constitutive androstane receptor levels in murine and human liver. Hepatology 46:209-18|
|Patel, Rushang D; Kim, Dae Joon; Peters, Jeffrey M et al. (2006) The aryl hydrocarbon receptor directly regulates expression of the potent mitogen epiregulin. Toxicol Sci 89:75-82|
|Ramadoss, Preeti; Marcus, Craig; Perdew, Gary H (2005) Role of the aryl hydrocarbon receptor in drug metabolism. Expert Opin Drug Metab Toxicol 1:9-21|
Showing the most recent 10 out of 13 publications