NOVEL FUNCTIONS OF THE AH RECEPTOR

芳香烃受体(AHR)是一种配体激活的转录 因素。2，3，7，8-四氯二苯并对二恶英(TCDD)和许多 多环芳香烃。(PAHs)被认为是由 它们对AHR的约束以及随后的一系列事件，包括： AHR与芳香烃受体核的联系 转位蛋白(ARNT)，与生成的异源二聚体结合 靶基因中的增强子序列，以及转录激活 靶基因。AHR领域的一个悬而未决的问题是AHR是否有 不依赖于其配基激活转录功能的活性 因素。在最近使用小鼠肝癌细胞的研究中，这些细胞被改造成 有不同的AHR含量，我们观察到AHR之间存在直接相关性 神经酰胺诱导细胞凋亡的含量和敏感性，但不是 星形孢菌素或阿霉素。神经酰胺不能作为AHR的配体。 此外，与所有已知的AHR介导的过程不同，易感性 神经酰胺诱导的细胞凋亡不需要有功能的ARNT。基于 这些观察结果，我们假设AHR是神经酰胺的调节剂 信令，并通过独立于其功能的进程来执行此操作 一种配体激活的、Arnt相关的转录因子。在这 应用程序我们建议确定AHR内容依赖的资源 我们注意到1)在具有不同AHR的各种细胞/组织类型中可见 内容；2)反映正反两方面的差异表达 凋亡蛋白。此外，4)我们将使用转基因分析和 AHR的截短或突变形式以确定区域/功能 (例如，DNA和配体/结合、异源二聚化、反式激活等) AHR在神经酰胺诱导的细胞凋亡中的重要调控作用。 这些研究将确定我们是否发现了一种新的功能 对于AHR，以及一种新的神经酰胺介导的信号调节器。是这样的 信息对发展、自身免疫和 多因素诱导细胞凋亡后的肿瘤个体发生与治疗 化疗药物似乎是神经酰胺依赖的，AHR表达 在胚胎发育和免疫细胞过程中受到严格调控 分化和激活。

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor. The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and many polycyclic aromatic hydrocarbons. (PAHs) are thought to be mediated by their binding to the AHR and a subsequent cascade of events including: association of the AHR with the aryl hydrocarbon receptor nuclear translocator (ARNT) protein, binding of the resultant heterodimer to enhancer sequencers in target genes, and transcriptional activation of the target genes. An unresolved issue in the AHR field is whether the AHR has activities independent of its function as a ligand-activated transcription factor. In recent studies employing murine hepatoma cells engineered to have different AHR contents we observed in direct correlation between AHR content and susceptibility to induction of apoptosis by ceramide, but not staurosporin or doxorubicin. Ceramide did not function as an AHR ligand. Furthermore, unlike all known AHR-mediated processes, susceptibility to ceramide-induced apoptosis did not require a functional ARNT. Based upon these observation we hypothesize that the AHR is a modulator of ceramide signaling, and does so by a process that is independent of it function is a ligand-activated, ARNT-associated transcription factor. In this application we propose to determine if the AHR content-dependent resources we noted are 1) seen in a variety of cell/tissue types having varied AHR contents; 2) reflect the differential expression of pro- and anti- apoptotic proteins. In addition, 4) we will use transfection analyses and truncated or mutated forms of the AHR to determine the regions/functions (e.g., DNA and ligand/binding, heterodimerization, transactivation, etc.) of the AHR important in the modulation of ceramide-induced apoptosis. These studies will establish whether we have identified a novel function for the AHR, and a new modulator of ceramide-mediated signaling. Such information is important to the areas of development, autoimmunity and cancer ontogeny and treatment since induction of apoptosis by many chemotherapeutic agents appears to ceramide-dependent, and AHR expression is tightly regulated during embryonic development and immune cell differentiation and activation.