In mammalian organisms, the xenobiotic-sensing receptors, CAR (constitutive androstane receptor;NR1I3) and PXR (pregnane X receptor;NR1I2), contribute critically as mediators of toxicological and physiological responses to chemical exposure. As nuclear receptors, both CAR and PXR function as transcriptional regulators for a large network of genes encoding a functional web of responses that include the metabolism and transport of xenobiotics, regulation of lipid and energy homeostasis, and modulation of cell proliferation. Mouse models of receptor biology have been deployed widely to characterize these features. Their importance notwithstanding, the mouse receptors are not equivalent to human. Among other aspects, the respective receptors differ fundamentally in their ligand specificity, encoded by marked variation in amino acid contact residues that define their ligand binding pockets. The receptors differ functionally as well, for example with CAR identified as necessary in the development of hepatocellular carcinoma in mice following promotion by non-genotoxic receptor activators, such as the direct ligand, TCPOBOP, or indirect activators such as phenobarbital (PB). However, extensive epidemiological studies in human populations have ascertained no excess risk of cancers following chronic PB exposures. Strikingly, CAR and PXR share overlapping as well as distinct preferences for their abilities to bind DNA targets. Surprisingly, results using chromatin immunoprecipitation and bioinformatics analyses have revealed extensive divergence among transcription factor binding sites between species. Species-selective splice variation in each receptor further defines inherent differences in species response. To allow biologically-based and scientifically defensible extrapolations of receptor function across mammalian species that accurately predict potential human toxicities, it is critical to delineate the molecular mechanisms underlying these differential responses. The central hypothesis of this research program is that unique biological roles contributed by mouse and human CAR, and PXR, are programmed at their most basic level by their respective dynamic and differential abilities to interact with their genomic targets. Further, we hypothesize that in humans, the CAR2 and CAR3 splice variants of CAR contribute an added layer of biological diversity, programmed in part through differential interaction with their own distinct DNA interactions. The strategies advanced entail the use of unique biological models and application of powerful and unbiased chromatin immunoprecipitation approaches, coupled with next-generating sequencing and bioinformatics analyses. Overall, these studies will reveal the global interactome bridged by these receptors, identifying both shared and distinct sites of receptor binding that ultimately drive the biological and toxicological functions contributed by these critical xenoreceptors across mammalian gene networks.
This research project will help define species specific factors at the genetic level that dictate differences in toxicological response. In particular the focus ison the role of regulatory receptors that are activated by chemical and pharmaceutical exposures that trigger compensatory responses in cells and tissues. The results will help better define modes of action that are specific to model organisms such as mice from those that are relevant to humans.
|Takeda, Shuso; Ikeda, Eriko; Su, Shengzhong et al. (2014) ?(9)-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: possible involvement of induced levels of PPAR? in MDA-MB-231 breast cancer cells. Toxicology 326:18-24|
|Chen, Tao; Laurenzana, Elizabeth M; Coslo, Denise M et al. (2014) Proteasomal interaction as a critical activity modulator of the human constitutive androstane receptor. Biochem J 458:95-107|
|Elcombe, Clifford R; Peffer, Richard C; Wolf, Douglas C et al. (2014) Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator. Crit Rev Toxicol 44:64-82|
|Wahlang, Banrida; Falkner, K Cameron; Clair, Heather B et al. (2014) Human receptor activation by aroclor 1260, a polychlorinated biphenyl mixture. Toxicol Sci 140:283-97|
|Currie, Richard A; Peffer, Richard C; Goetz, Amber K et al. (2014) Phenobarbital and propiconazole toxicogenomic profiles in mice show major similarities consistent with the key role that constitutive androstane receptor (CAR) activation plays in their mode of action. Toxicology 321:80-8|
|Chen, Fengming; Zamule, Stephanie M; Coslo, Denise M et al. (2013) The human constitutive androstane receptor promotes the differentiation and maturation of hepatic-like cells. Dev Biol 384:155-65|
|Castino, Roberta; Fiorentino, Ilaria; Cagnin, Monica et al. (2011) Chelation of lysosomal iron protects dopaminergic SH-SY5Y neuroblastoma cells from hydrogen peroxide toxicity by precluding autophagy and Akt dephosphorylation. Toxicol Sci 123:523-41|
|Omiecinski, Curtis J; Vanden Heuvel, John P; Perdew, Gary H et al. (2011) Xenobiotic metabolism, disposition, and regulation by receptors: from biochemical phenomenon to predictors of major toxicities. Toxicol Sci 120 Suppl 1:S49-75|
|Omiecinski, Curtis J; Coslo, Denise M; Chen, Tao et al. (2011) Multi-species analyses of direct activators of the constitutive androstane receptor. Toxicol Sci 123:550-62|
|Zamule, Stephanie M; Coslo, Denise M; Chen, Fengming et al. (2011) Differentiation of human embryonic stem cells along a hepatic lineage. Chem Biol Interact 190:62-72|
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