NOVEL FUNCTIONS OF THE AH RECEPTOR

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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.