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

Carcinogenesis. 2004 Aug;25(8):1467-75. doi: 10.1093/carcin/bgh135. Epub 2004 Mar 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cadmium / metabolism*
  • Cell Line, Tumor
  • Cell Survival
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • DNA-Binding Proteins / biosynthesis*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Female
  • Flavonoids / pharmacology
  • Gene Expression Regulation*
  • Genes, Reporter
  • Humans
  • Immunohistochemistry
  • Inflammation
  • Isoquinolines / pharmacology
  • Lung / pathology
  • Mitogen-Activated Protein Kinases / metabolism
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Nucleic Acid Hybridization
  • Plasmids / metabolism
  • Precipitin Tests
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2*
  • Rats
  • Rats, Wistar
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Sulfonamides*
  • Time Factors
  • Transcription Factors / biosynthesis*
  • Transfection
  • bcl-2-Associated X Protein


  • BAX protein, human
  • Bax protein, rat
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Flavonoids
  • Isoquinolines
  • NR4A1 protein, human
  • Nr4a1 protein, rat
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Sulfonamides
  • Transcription Factors
  • bcl-2-Associated X Protein
  • Cadmium
  • Cyclic AMP-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one