Polycyclic aromatic hydrocarbons (PAH) are a class of environmental chemicals that are known to cause toxicity and cancers in humans. The molecular changes induced by exposure to PAH are mediated by the aryl hydrocarbon receptor (AHR). In particular, the AHR mediates up-regulation of phase I and phase II xenobiotic metabolizing enzymes that can cause both bioactivation and detoxification of PAH. Indeed, there is a fine balance between bioactivation and detoxification of chemical carcinogens that are directly influenced by AHR-dependent signaling. Emerging evidence indicates that PPAR?/? may modulate AHR activity in skin/keratinocytes, and that this interaction will significantly alter the balance between bioactivation and detoxification leading to differences in the susceptibility to chemically-induced toxicity.
For Specific Aim 1, we will determine the mechanisms by which PPAR?/? can modulate AHR activity with an emphasis on receptor heterodimer translocation and critical transcriptional events necessary for increasing expression of xenobiotic metabolism that are necessary for bioactivation and detoxification of PAH.
For Specific Aim 2, we will determine if PPAR?/? can functionally alter PAH-induced skin carcinogenesis mediated by AHR. Results from these studies will elucidate novel regulatory mechanisms of AHR-dependent signaling that are central in mediating the toxic and carcinogenic effects caused by exposure to environmental PAH. Importantly, results from these studies might help explain the significant variation in AHR-dependent function in humans, since no functional polymorphisms in the Ahr have been identified.
Exposure to environmental chemicals such as polycyclic aromatic hydrocarbons can cause toxicity and cancers in humans, with associated costs exceeding $100 billion annually. The causes of chemically-induced toxicity and cancer are very unclear. Thus, it is essential to determine the mechanisms underlying chemically-induced toxicity and carcinogenesis. While it is well accepted that the aryl hydrocarbon receptor is required to mediate cellular changes that can both cause (bioactivation) and prevent (detoxification), emerging evidence suggests that other proteins may also affect AHR activity. In these studies, we will examine new proteins that may interact with AHR signaling and identify novel pathways that may modulate chemically- induced toxicity and cancers.
|Peters, Jeffrey M (2017) Flipping a citrate switch on liver cancer cells. J Biol Chem 292:13902-13903|
|Yao, Pei-Li; Morales, Jose L; Gonzalez, Frank J et al. (2017) Peroxisome proliferator-activated receptor-?/? modulates mast cell phenotype. Immunology 150:456-467|
|Yao, Pei-Li; Chen, Liping; Dobrza?ski, Tomasz P et al. (2017) Peroxisome proliferator-activated receptor-?/? inhibits human neuroblastoma cell tumorigenesis by inducing p53- and SOX2-mediated cell differentiation. Mol Carcinog 56:1472-1483|
|Koga, Takayuki; Yao, Pei-Li; Goudarzi, Maryam et al. (2016) Regulation of Cytochrome P450 2B10 (CYP2B10) Expression in Liver by Peroxisome Proliferator-activated Receptor-?/? Modulation of SP1 Promoter Occupancy. J Biol Chem 291:25255-25263|
|Hubbard, Troy D; Murray, Iain A; Bisson, William H et al. (2015) Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles. Sci Rep 5:12689|
|Peters, Jeffrey M; Yao, Pei-Li; Gonzalez, Frank J (2015) Targeting Peroxisome Proliferator-Activated Receptor-?/? (PPAR?/?) for Cancer Chemoprevention. Curr Pharmacol Rep 1:121-128|
|Peters, Jeffrey M; Gonzalez, Frank J; Müller, Rolf (2015) Establishing the Role of PPAR?/? in Carcinogenesis. Trends Endocrinol Metab 26:595-607|
|Yao, Pei-Li; Chen, Li Ping; Dobrza?ski, Tomasz P et al. (2015) Inhibition of testicular embryonal carcinoma cell tumorigenicity by peroxisome proliferator-activated receptor-?/?- and retinoic acid receptor-dependent mechanisms. Oncotarget 6:36319-37|
|Yao, Pei-Li; Chen, LiPing; Hess, Rex A et al. (2015) Peroxisome Proliferator-activated Receptor-D (PPARD) Coordinates Mouse Spermatogenesis by Modulating Extracellular Signal-regulated Kinase (ERK)-dependent Signaling. J Biol Chem 290:23416-31|
|Zhu, Bokai; Ferry, Christina H; Markell, Lauren K et al. (2014) The nuclear receptor peroxisome proliferator-activated receptor-?/? (PPAR?/?) promotes oncogene-induced cellular senescence through repression of endoplasmic reticulum stress. J Biol Chem 289:20102-19|
Showing the most recent 10 out of 27 publications