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

描述（由申请人提供）：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（二恶英）和 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。在结合配体后，AHR与配体二聚化。 芳香烃核受体转运蛋白（ARNT）。AHR/ARNT 然后，二聚体激活参与异生素合成的几个基因的转录。 新陈代谢.然而，有证据表明，配体AHR可以触发生物学， 通过不涉及ARNT的信号转导途径的反应。这 该提案利用了最近衍生的Arnt条件性敲除小鼠 （对于一个foxed Arnt等位基因是纯合的），其中Arnt可以被敲除（在 特定组织），以调查是否需要ARNT（1） 二恶英诱导胸腺退化（已知其依赖于 （2）BP的（AHR依赖性）完全致癌活性，（3） TCDBF和/或二恶英的AHR依赖性肿瘤促进活性，和（4）TCDBF和/或二恶英的AHR依赖性肿瘤促进活性， BP的致瘤活性。这些调查应该有助于了解 AHR配体诱导毒性和癌症的分子机制。 低氧诱导因子（HIF 1）是低氧诱导的主要调节因子， 反应，引发许多适应性反应缺氧，包括 血管生成HIF-1由ARNT和HIF-1 α的二聚体组成。固体中的许多细胞 肿瘤存在于缺氧状态。关于HIF-1是否 介导的低氧反应加速或延缓肿瘤生长。利用 Arnt条件性敲除小鼠，Specific aim 5将通过以下方式解决该问题： 比较内源性肿瘤诱导的生长速率和血管生成反应， 在ARNT阴性和ARNT阳性宿主细胞中。具体目标6将调查 当在肿瘤发展过程中HIF- 1活性影响（积极或消极）时， 阴性）肿瘤生长。这将通过比较生长动力学来解决 和内源性肿瘤的血管生成的诱导破坏之前和之后， foxed Arnt基因，并通过研究肿瘤异种移植产生的 其中ARNT表达可由四环素调节的肿瘤发生细胞。

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.