NOVEL FUNCTIONS OF THE AH RECEPTOR

芳香烃受体（aryl hydrocarbon receptor，AHR）是一种配体激活的转录因子， 因子2，3，7，8-四氯二苯并对二恶英（TCDD）和许多 多环芳烃（多环芳烃）被认为是介导的 它们与AHR的结合以及随后的级联事件，包括： AHR与芳香烃受体核的结合 转运蛋白（ARNT）蛋白，将所得异二聚体结合至 靶基因中的增强子序列，以及增强子序列的转录激活。 靶基因AHR领域的一个悬而未决的问题是AHR是否具有 活性独立于其作为配体激活转录的功能 因子在最近的研究中，采用小鼠肝癌细胞工程， 不同的AHR含量，我们观察到AHR之间的直接相关性 含量和神经酰胺诱导凋亡的敏感性，但不是 星形孢菌素或阿霉素。神经酰胺不起AHR配体的作用。 此外，与所有已知的AHR介导的过程不同， 神经酰胺诱导的细胞凋亡不需要功能性ARNT。基于 根据这些观察，我们假设AHR是神经酰胺的调节剂 信号，并通过一个独立于它的功能的过程来完成， 配体激活的ARNT相关转录因子。在这 应用程序，我们建议，以确定是否AHR内容相关的资源 我们注意到：1）在具有不同AHR的各种细胞/组织类型中可见 2）反映了前、抗- 凋亡蛋白此外，4）我们将使用转染分析， AHR的截短或突变形式，以确定区域/功能 (e.g., 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的调节中起重要作用。 这些研究将确定我们是否发现了一种新的功能， 和神经酰胺介导的信号传导的新调节剂。等 信息对于发育、自身免疫和 癌症个体发生和治疗，因为许多细胞凋亡的诱导 化疗药物似乎神经酰胺依赖性，AHR表达 在胚胎发育和免疫细胞发育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.