Ap1 A Molecular Switch For Asbestosinduced Carcinogenesis

Heintz et al.172 first demonstrated that asbestos activates AP-1 transcription factor by inducing persistent expression of c-fos and c-jun genes in rat pleural mesothelial cells and hamster tracheal epithelial cells. In AP-1-luciferase reporter transgenic mice, asbestos activates AP-1 in both lung and bronchial tissues.173 This activation of AP-1 by asbestos is persistent until day three after a single dose of crocidolite asbestos exposure. Further studies suggested that PKCa plays a critical role in asbestos-induced c-fos and c-jun expression, since a PKCa inhibitor substantially decreased c-fos and c-jun mRNA in asbestos-treated cells.174 In addition, asbestos is also capable of inducing expression of fra-1, a gene encoding another AP-1 subunit, Fra, in rat mesothelial cells in a dose-dependent manner.175 A recent study by Ramos-Nino et al.176 demonstrated that the fra-1 induction by asbestos in mesothelial cell transformation is dependent on the activation of extracellular signal-regulated kinases (ERKs 1/2). Inhibition of ERK activation or fra expression reversed the transformed phenotype of mesothelioma cells, suggesting that fra-1 induction is the most important event in asbestos-induced carcinogenic transformation.

In addition to the induction of AP-1 subunit genes, asbestos activates AP-1 through the upstream kinases that are responsible for the phosphorylation of AP-1 subunits and enhancement of AP-1 transcriptional activity. Asbestos activates ERK1 and ERK2 through EGF-R.177 Pretreatment of the cells with tyrphostin AG1478, a specific inhibitor of the tyrosine kinase activity of EGF-R, substantially decreased phosphorylation and activation of ERK1 and/or ERK2 induced by asbestos. The mechanism of how asbestos affects the function of EGF-R is elusive. Asbestos has been shown to be able to interrupt the interaction of EGF and its receptor, and at the same time to increase the protein expression of EGF-R.178 The activation of ERK1 or ERK2 was generally in response to cell growth signals that induce cell proliferation. Intriguingly, asbestos is also capable of inducing cell apoptosis through the activation of ERK.178 The ability of asbestos to cause kinase activation was largely attributed to its induction of ROS. However, a discrepancy was noted between asbestos and H2O2 in their stimulation on ERK and JNK, a stress and apoptotic MAP kinase.179 In rat pleural mesothelial cells, H2O2 activates both ERK and JNK, whereas asbestos activates only ERK but not JNK.179 The activation of p38 MAP kinase by asbestos appears to be responsible for asbestos-induced cytokine release from normal human alveolar macrophages.180

The DNA binding activity of AP-1 can be regulated by asbestos through the inducible nuclear translocation of redox factor-1 (Ref-1, APEX) in human alveolar macrophages or murine macrophage cells treated with low concentrations of asbestos.181 In rat pleural mesothelial cells, asbestos induces increased levels of Ref-1 mRNA and protein in a dose-dependent manner.182 Ref-1 is a nuclear protein possessing both DNA repair activity and redox regulatory activity, and the latter may be critical for the DNA binding activity of AP-1.183 The DNA binding activity of AP-1 is partially dependent on the redox status of the conserved cysteine residues in the DNA binding domain of c-Jun and c-Fos proteins. Association of Ref-1 with AP-1 causes reduction of these cysteines and enhances the DNA binding activity of AP-1.184

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