Coordination of JNK1 and JNK2 Is Critical for GADD45α Induction and Its Mediated Cell Apoptosis in Arsenite Responses

Arsenite is a well documented environmental pathogen, whereas it has also been applied as medication to treat various neoplasmas. The pathogenic and therapeutic effects of arsenite are associated with cellular apoptotic responses. However, the molecular mechanisms of arsenite-induced apoptosis are not very well understood. Our previous study has shown that arsenite exposure is able to activate JNKs, which subsequently mediate the apoptotic outcome. The present study further revealed that the coordination of JNK1 and JNK2 was critical for the arsenite-induced expression of GADD45 alpha ( growth arrest and DNA damage 45 alpha), which in turn mediated the cellular apoptosis. The arsenite-induced apoptosis and GADD45 alpha expression were significantly impaired in mouse embryonic fibroblasts deficient in either jnk1 (JNK1(-/-)) or jnk2 (JNK2(-/-)). Knockdown of GADD45 alpha by its specific small interfering RNA also dramatically reduced the apoptotic responses, and overexpression of GADD45 alpha in either JNK1(-/-) or JNK2(-/-) mouse embryonic fibroblasts partially resensitized the cell death. Furthermore, it was found that the regulation of GADD45 alpha by JNK1 and JNK2 was achieved through mediating the activation of c-Jun, since in the JNK1(-/-) and JNK2(-/-) cells the c-Jun activation was impaired, and overexpression of the dominant negative mutant of c-Jun (TAM67) in wild type cells could also block GADD45 alpha induction as well as cellular apoptosis. Our results demonstrate that the coordination of JNK1 and JNK2 is critical for c-Jun/GADD45 alpha-mediated cellular apoptosis induced by arsenite.