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Dioxin Suppresses the Checkpoint Protein, MAD2, by an Aryl Hydrocarbon Receptor-independent Pathway¹

Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation [K. O., T. O., R. I., A. K., K. E., Y. F-K., M. K.]; Department of Pathology, Tokyo Medical University, Tokyo 160-8402 [K. O., T. O., R. I., A. K., K. E., K. I., M. K., K. M.]; and Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578 [J. M., Y. F-K.], Japan

The compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown recently to be carcinogenic, but little is currently known about the molecular mechanism of TCDD affecting cell proliferation and carcinogenesis. In this report, we demonstrate that TCDD suppresses the expression of the checkpoint protein, Mad2. Suppression of Mad2 was also observed in aryl hydrocarbon receptor-deficient mouse embryonic fibroblasts, suggesting that TCDD suppresses Mad2 by a novel TCDD receptor signaling mechanism. In addition, HeLa cells treated with TCDD failed to arrest in mitosis after nocodazole treatment. The Mad2 protein plays a significant role in accurate chromosome segregation in mitotic cells. Our data suggest that TCDD may increase chromosomal instability through the suppression of Mad2 expression.

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