The aryl hydrocarbon receptor (AHR) binds a variety of pollutants, including benzo(a)pyrene (BP), 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) and 2,3,7,8-tetrachlorodibenzofuran (TCDBF), and mediates the carcinogenic and toxic effects of these compounds. After binding ligand, AHR dimerizes with the Aryl Hydrocarbon Nuclear Receptor Translocator Protein (ARNT). The AHR/ARNT dimer then activates transcription of several genes involved in xenobiotic metabolism. However, there is evidence that liganded AHR can trigger biological responses via signal transduction pathways that do not involve ARNT. This proposal takes advantage of a recently derived Arnt conditional knockout mouse (homozygous for a foxed Arnt allele) in which Arnt can be knocked out (in specific tissues) in adulthood, to investigate whether ARNT is required for (1) the induction of thymic involution by dioxin (which is known to be dependent on AHR), (2) the (AHR-dependent) complete carcinogenic activity of BP, (3) the AHR-dependent tumor promoting activity of TCDBF and/or dioxin, and (4) the tumor initiating activity of BP. These investigations should shed light on the molecular mechanisms whereby AHR ligands induce toxicity and cancer. Hypoxia-Inducible Factor (HIF1) is the master regulator of the hypoxic response, triggering many adaptive responses to hypoxia, including angiogenesis. HIF-1 consists of a dimer of ARNT and HIF-la. Many cells in solid tumors exist in a hypoxic state. It is controversial as to whether the HIF-l mediated hypoxic response accelerates or retards tumor growth. Utilizing the Arnt conditional knockout mouse, Specific aim 5 will address this issue by comparing the growth rate and angiogenic response of endogenous tumors induced in ARNT-negative and ARNT-positive host cells.
Specific aim 6 will investigate when during tumor development HIF- 1 activity affects (either positively or negatively) tumor growth. This will be addressed by comparing growth kinetics and angiogenesis of endogenous tumors before and after inducing disruption of the foxed Arnt gene, and by studying tumor xenografts generated from tumorogenic cells in which ARNT expression can be modulated by tetracycline.
|Vardabasso, Chiara; Gaspar-Maia, Alexandre; Hasson, Dan et al. (2015) Histone Variant H2A.Z.2 Mediates Proliferation and Drug Sensitivity of Malignant Melanoma. Mol Cell 59:75-88|
|Qian, Meng; Ma, Michelle W; Fleming, Nathaniel H et al. (2013) Clinicopathological characteristics at primary melanoma diagnosis as risk factors for brain metastasis. Melanoma Res 23:461-7|
|Morsi, Amr; Gaziel-Sovran, Avital; Cruz-Munoz, William et al. (2013) Development and characterization of a clinically relevant mouse model of melanoma brain metastasis. Pigment Cell Melanoma Res 26:743-5|
|Segura, Miguel F; Greenwald, Holly S; Hanniford, Doug et al. (2012) MicroRNA and cutaneous melanoma: from discovery to prognosis and therapy. Carcinogenesis 33:1823-32|
|Shi, S; Yoon, D Y; Hodge-Bell, K et al. (2010) Aryl hydrocarbon nuclear translocator (hypoxia inducible factor 1beta) activity is required more during early than late tumor growth. Mol Carcinog 49:157-65|
|Shi, Shengli; Yoon, Diana Y; Hodge-Bell, Kimberly C et al. (2009) The aryl hydrocarbon receptor nuclear translocator (Arnt) is required for tumor initiation by benzo[a]pyrene. Carcinogenesis 30:1957-61|