ARNT:Roles in Tumor Induction and Growth, and Toxicity.

描述(申请人提供)：芳香烃受体(AHR)结合 各种污染物，包括苯并(A)芘(BP)， 2，3，7，8-四氯二苯并对二恶英 2，3，7，8-四氯二苯并呋喃(TCDBF)，并介导致癌和 这些化合物的毒性作用。在与配体结合后，AHR与 芳烃核受体转位蛋白(ARNT)。AHR/ARNT 然后，二聚体激活与外源生物有关的几个基因的转录 新陈代谢。然而，有证据表明，连接的AHR可以引发生物 通过不涉及ARNT的信号转导途径作出反应。这 Proposal利用最近衍生的Arnt条件性基因敲除小鼠 (对于狐狸Arnt等位基因来说是纯合的)Arnt可以被敲除的(in 特定组织)，以调查(1)是否需要ARNT 二恶英诱导胸腺退化(已知依赖于 AHR)，(2)BP的(AHR依赖)完全致癌活性，(3) TCDBF和/或二恶英对AHR依赖的促癌活性，以及(4) BP的肿瘤启动活性。这些调查应该会揭示 AHR配体诱导毒性和癌症的分子机制。 低氧诱导因子(HIF1)是低氧的主要调节因子 反应，触发许多对低氧的适应性反应，包括 血管生成。HIF-1由Arnt和HIF-1a的二聚体组成。固体中的许多细胞 肿瘤处于缺氧状态。低氧是否会引发争议--L 介导的缺氧反应加速或延缓了肿瘤的生长。利用 ArnT条件性基因敲除鼠标，SPICAL AIM 5将通过以下方式解决此问题 内源性肿瘤的生长速度和血管生成反应的比较 在ArnT阴性和ArnT阳性宿主细胞中。特定目标6将调查 在肿瘤发展过程中，HIF-1活性何时影响(无论是积极的还是 阴性)肿瘤生长。这将通过比较增长动力学来解决。 诱导阻断前后内源性肿瘤血管生成的变化 狐狸Arnt基因，并通过研究产生的异种肿瘤 四环素可调节Arnt表达的肿瘤细胞。

DESCRIPTION (provided by applicant): 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.