Aryl hydrocarbon receptor activation by cAMP vs. dioxin: Divergent signaling pathways

Even before the first vertebrates appeared on our planet, the aryl hydrocarbon receptor (AHR) gene was present to carry out one or more critical life functions. The vertebrate AHR then evolved to take on functions of detecting and responding to certain classes of environmental toxicants. These environmental pollutants include polycyclic aromatic hydrocarbons (e.g., benzo[a]pyrene), polyhalogenated hydrocarbons, dibenzofurans, and the most potent small-molecular-weight toxicant known, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin). After binding of these ligands, the activated AHR translocates rapidly from the cytosol to the nucleus, where it forms a heterodimer with aryl hydrocarbon nuclear translocator, causing cellular responses that lead to toxicity, carcinogenesis, and teratogenesis. The nuclear form of the activated AHR/aryl hydrocarbon nuclear translocator complex is responsible for alterations in immune, endocrine, reproductive, developmental, cardiovascular, and central nervous system functions whose mechanisms remain poorly understood. Here, we show that the second messenger, cAMP (an endogenous mediator of hormones, neurotransmitters, and prostaglandins), activates the AHR, moving the receptor to the nucleus in some ways that are similar to and in other ways fundamentally different from AHR activation by dioxin. We suggest that this cAMP-mediated activation may reflect the true endogenous function of AHR; disruption of the cAMP-mediated activation by dioxin, binding chronically to the AHR for days, weeks, or months, might be pivotal in the mechanism of dioxin toxicity. Understanding this endogenous activation of the AHR by cAMP may help in developing methods to counteract the toxicity caused by numerous environmental and food-borne toxic chemicals that act via the AHR

Characterization of two nuclear proteins that interact with cytochrome P-450 1A2 mRNA - Regulation of RNA binding and possible role in the expression of the Cyp1a2 gene

Regulation of the expression of the cytochrome P-450 1a2 gene (cyp1a2) occurs mainly at the transcriptional level, but the molecular events involved in the induction process are partly unknown. Some reports have proposed involvement of post-transcriptional mechanisms [Adesnik, M. and Atchison, M. (1986) Crit. Rev. Biochem. 19, 247-305; Silver, G. and Krauter, K.S. (1990) Mol. Cell. Biol. 10, 6765-6768]. Here we report the identification of two proteins in the nuclear fraction of mouse liver, with specific binding characteristics towards CYP1A2 mRNA. The proteins have apparent molecular masses of 37 kDa and 46 kDa and exhibit a high affinity for a poly(U) motif in the 3' untranslated region of CYP1A2 mRNA; This motif seems to be important for their specific and apparently competitive binding to CYP1A2 mRNA. Treatment of mice with an inducer of CYP1A2, 3-methylcholanthrene, increases the binding of the 46-kDa protein and decreases the binding of the 37-kDa protein to the mRNA, suggesting that changes in the binding of the proteins to the mRNA could play a role in the upregulation of CYP1A2 mRNA by 3-methylcholanthrene. Phosphorylation of the 46-kDa protein, or of an intermediary factor, may play a role in its binding activity. Furthermore, the 46-kDa but not the 37-kDa protein is recognized by a monoclonal antibody against the heterogeneous nuclear ribonucleoprotein C, a nuclear protein probably involved in pre-mRNA processing. While more work is needed to understand the function of the proteins that bind to the 3' untranslated region of CYP1A2, it is possible that the 37-kDa protein has a role in the maintenance of uninduced levels of CYP1A2 mRNA, while the 46-kDa protein could be important in the maturation of elevated levels of CYP1A2 pre-mRNA, during induction