Eventhough, both c-Jun NH2-terminal kinases (JNKs) and extracellular signal-regulated protein kinases (Erks) were activated by arsenite, their activation varied temporally and depending on the dosage. Significant activation of Erks was observed 15 min after exposure and at all dosages studied, whereas no induction of Erks by arsenite occurred after a 30-min exposure. On the other hand, activation of JNKs by arsenic was observed only at a relatively high dosage (>50 ?M) and after 60 min of exposure.
Arsenic Induces AP-1 Activation in Cells and AP-1-Luciferase Transgenic Mice
Transactivation of AP-1 was seen in JB6 cells by both arsenite and arsenate. Since increased activation of AP-1 by arsenite could be inhibited by either treating cells with MAP kinase Erk kinase (MEK)1 inhibitor, or overexpression of dominant-negative PKC?, this induction appears to occur through activation of mitogen-activated protein (MAP) kinases and protein kinase C (PKC). Moreover, in AP-1-luciferase reporter transgenic mice, transactivation of AP-1 was caused by both arsenite and arsenate.
Inhibition of Erks Activation Blocks Arsenic-Induced Cell Transformation
Various results also indicate that Erk activation but not JNK activation is required for arsenite-induced cell transformation as evidenced by the usage of dominant-negative Erk2-K52R stable transfectants.
Inhibition of JNKs Blocks Arsenic Induced Apoptosis
Expression of the dominant-negative mutant JNK1 blocked induction of apoptosis by arsenite or arsenate compared with vector-transfected JB6 cells, indicating the role of activation of JNKs in arsenic-induced apoptosis
p53 Is Not Involved in Induction of Apoptosis by Arsenic
In Cl 41 p53 cells treated with a wide dose range of arsenic, Arsenic had no effect on p53-dependent transcription activation, suggesting that p53 may not have a role in arsenic-induced apoptosis. In studies involving two fibroblast cell lines derived from mouse embryos either containing wild-type p53 (p53+/+) or deficient in p53 (p53–/–), treatment with arsenite or arsenate results in apoptosis in both cell lines. Arsenic is also able to induce apoptosis in tumor cells independently of p53 activation and thus could be specifically directed against p53-defective cancer cells, therefore becoming effective in counteracting drug resistance in p53-deficient cancers.
Involvement of PKC in Arsenic Induced Signal Transduction