Carcinogenesis Advance Access originally published online on March 11, 2004
Carcinogenesis 2004 25(8):1467-1475; doi:10.1093/carcin/bgh135
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Carcinogenesis vol.25 no.8 © Oxford University Press 2004; all rights reserved.
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Induction of orphan nuclear receptor Nur77 gene expression and its role in cadmium-induced apoptosis in lung
Department of Bioscience and Biotechnology, Sejong University, Seoul 143-747, 1 College of Pharmacy, Wonkwang University, Jeonbuk 570-749, 2 School of Medicine, Chung-Ang University, Seoul 110-799, 3 PhamacoGenechips Inc., Kangwon 200-160 and 4 College of Pharmacy, Seoul National University, Seoul 110-799, Korea
5 To whom correspondence should be addressed Email: molee{at}sejong.ac.kr
Cadmium is an environmentally widely dispersed and highly toxic heavy metal that has been classified as a human carcinogen. Using the suppression subtractive hybridization technique, we identified previously 29 cadmium-inducible genes, primarily involved in inflammation, cell survival and apoptosis. Among these genes, we are particularly interested in Nor-1, because this gene belongs to the Nur77 family, which plays a key role in the apoptotic processes of a variety of cells and tissues, including the lung. In the present study, we characterized the induction of the Nur77 family genes in the lungs after cadmium exposure. Nur77, Nor-1 and Nurr1 were all induced after cadmium treatment in a dose- and time-dependent manner in WI-38 and A549 lung cell lines. Treatment with inhibitors of signaling pathways, such as PD98059 and H89, almost completely blocked the expression of Nur77, indicating that the extracellular signal-regulated kinase and protein kinase A signaling pathways are important in cadmium-induced Nur77 expression. When a plasmid encoding dominant-negative Nur77 was transfected into A549 cells, cadmium-induced apoptotic changes, such as chromosomal condensation and Bax expression, were significantly reduced, suggesting that the expression of Nur77 plays an important role in cadmium-induced apoptosis. Furthermore, the number of apoptotic cells and the expression of Nur77 was increased in lung tissues collected from cadmium-treated (30 µmol/kg body wt) Wistar rats. Taken together, these results demonstrate that cadmium induces the expression of Nur77 family genes, leading to apoptosis in lung cells, which may cause pulmonary toxicity in response to cadmium exposure.
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