Induction of orphan nuclear receptor Nur77 gene expression and its role in cadmium-induced apoptosis in lung

Abstract

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 micromol/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.

Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial Cells

“…It has been shown that Nur77 is expressed in lung epithelial cells and causes epithelial cell apoptosis following exposure to cadmium. However, the impact of Nur77 in inflammation in epithelial cells was not investigated (37). In the present study, we found that overexpression of Nur77 in airway epithelial cells resulted in a marked reduction in expression levels of diverse proinflammatory cytokines.…”

p53 and Nur77/TR3 – transcription factors that directly target mitochondria for cell death induction

“…Inhibition of Nur77 expression by antisense RNA prevents the apoptotic effect of AHPN/CD437. Rapid induction of Nur77 also occurs in cancer cells after stimulation of apoptosis by a variety of apoptosis-inducing agents, including calcium ionophores, etoposide (VP-16) (Li et al, 2000;Liu, 2002), and phorbol ester (Li et al, 2000;Liu, 2002;Cao et al, 2004a;Lin et al, 2004b), synthetic chenodeoxycholic acid derivatives (Jeong et al, 2003), Di-n-butyltin dichloride (Gennari et al, 2002), histone deacetylase inhibitors (Chinnaiyan et al, 2006), cadmium (Shin et al, 2004), 1,1-bis(3 0 -indolyl)-1-(p-substituted phenyl)-methanes (Chintharlapalli et al, 2005), and induced Nur77 contributes to their apoptotic effects.…”

Cardenolides from Antiaris toxicaria as Potent Selective Nur77 Modulators

“…3) Rapid induction of Nur77 has since been observed in cancer cells after stimulation of apoptosis by a variety of apoptosis-inducing agents, including calcium ionophores, etoposide (VP-16), 4,5) phorbol ester, [4][5][6][7] synthetic chenodeoxycholic acid derivatives, 8) di-n-butyltin dichloride, 9) histone deacetylase inhibitors, 10) cadmium, 11) and 1,1-bis(3Ј-indolyl)-1-(p-substituted phenyl)methanes.…”