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Dioxin suppresses the checkpoint protein, MAD2, by an aryl hydrocarbon receptor-independent pathway
K Oikawa1, T Ohbayashi, J Mimura
1Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Tokyo 160-8402, Japan.
Abstract:
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.
Insights
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses the expression of the cell cycle checkpoint protein Mad2. This TCDD-induced suppression may lead to increased chromosomal instability and contribute to carcinogenesis.
Area of Science:
- Molecular toxicology
- Cell biology
- Carcinogenesis research
Background:
- 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a known carcinogen.
- The molecular mechanisms underlying TCDD's effects on cell proliferation and cancer are not fully understood.
Purpose of the Study:
- To investigate the molecular mechanism of TCDD's effect on cell proliferation and carcinogenesis.
- To determine if TCDD affects the expression of cell cycle checkpoint proteins.
Main Methods:
- Treated HeLa cells and aryl hydrocarbon receptor-deficient mouse embryonic fibroblasts with TCDD.
- Assessed the expression levels of the checkpoint protein Mad2.
- Evaluated mitotic arrest in nocodazole-treated cells.
Main Results:
- TCDD treatment suppressed the expression of Mad2 in a TCDD receptor-dependent manner.
- HeLa cells treated with TCDD failed to arrest in mitosis after nocodazole exposure.
- Mad2 protein is crucial for accurate chromosome segregation during mitosis.
Conclusions:
- TCDD suppresses Mad2 expression via a novel receptor signaling pathway.
- TCDD-induced suppression of Mad2 may disrupt accurate chromosome segregation.
- This disruption could lead to increased chromosomal instability and contribute to TCDD's carcinogenic effects.