The Ah or dioxin receptor (AhR) is an active transcriptional factor that when activated in the presence of ligand translocates to nucleus and couples with the nuclear aryl hydrocarbon hydroxylase nuclear translocator (ARNT) protein. This active AhR complex is capable of binding to enhancer sequences that lead to the stimulation of gene transcription. The treatment of animals with polyclic aromatic hydrocarbons (PAHs) or heterocyclic aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) associate with the AhR and stimulate transcriptional activation of the CYP1A1 and CYP1A2 genes. While there is significant information regarding the action: of the AhR on the activation of the CYP1A1 gene, we have been the sole laboratory to map the regulatory elements associated with the induction of the human CYP1A2 gene. As are outlined in preliminary results, it has also been observed that the transcriptional activity of the human CYP1A1 gene by the AhR is greatly enhanced when cells are exposed to PKC activators. In addition., the appearance of the AhR complex in the nucleus is completely blocked when PKC activity is inhibited. Since there are no TRE or Jun/AP1 binding sites in the regulatory regIon of the CYP1A1 gene, this result indicates that the activity of the AhR complex is influenced dramatically by cellular events that are under the control of PKC. Since transcriptional induction of the CYP1 genes are under the regulation of the AhR, experiments will be undertaken to determine if Jun/AP1 factors facilitate AhR activity. Other cellular events that influence nuclear migration of the AhR complex will be also examined, since PKC activity may control this event. In addition. the outcome of these experiments are predicted to be of value in examining the molecular events that underlie the expression of CYP1A2 gene since this gene has been predicted to be under the regulation of the AhR.
