Study on clarification of unregulated gene expression to genome network by dioxin and related compounds using a human alveolar carcinoma cell line

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The arylhydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates a spectrum of toxic and biological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) and related compounds. Although the physiological ligand for the AhR has not yet been identified, several reports have suggested that the AhR may play important roles not only in the regulation of xenobiotic metabolism but also in the maintenance of homeostatic functions.In this study, we first investigated the role of AhR on cell proliferation. The cell proliferation of A549 cells, a human alveolar carcinoma cell line, was enhanced by the treatment with the AhR-ligand, β -naphthoflavone. The enhancement effect was disappeared by the co-treatment with the AhR-antagonist, α-naphthoflavone. Next, in order to obtain direct evidence that the AhR regulates cell proliferation, we isolated the clones that overexpress the AhR. These clones grow faster than control cells, and the rate of growth is proportional to t … More he amount of the AhR. Cell cycle analysis revealed that the acceleration of cell growth by overexpression of the AhR is most probably due to shortening of the late M to S phases. Studies on the expression profiles of cell cycle regulators showed that the AhR or AhR ligand induces the expression of DP2, PCNA, and RFC38. DP2 is the transcription factor that forms the functional dimer with E2F and regulates the expression of several genes involved in DNA synthesis. Interestingly, both PCNA and RFC38 are target genes of E2F and the DP complex. E2F activity was substantially increased in both the AhR-overexpressing cells and the AhR-agonist treated cells, suggesting that AhR-activated E2F/DP2 may induce the expression of PCNA and RFC38 and subsequent DNA synthesis. Down-regulation of the expression of the Arnt by RNAi diminished the effects of the AhR on the cell proliferation of the A549 cells. Consequently, we conclude that the AhR, presumably in collaboration with the Arnt, activates the DNA synthesis and the subsequent cell proliferation in A549 cells. Less