Arsenic is one of the heavy metals that are harmful to living organisms and is known to induce multiple stress responses. It has been reported that arsenic selectively activates
p38 MAP kinase (MAPK) in mammalian cultured cells, but the relationship between
p38 and arseical resistance in muticellular organisms remained to be determined. To address this, we have studied the role of the
p38 MAPK pathway on arsenical-induced cellular response in C. elegans as a model system. In wild-type N2 worms, sodium arsenite strongly induced activation of C. elegans
p38 PMK-1. RNAi of
pmk-1 lowered the resistance of animals to arsenite. Thus,
p38 MAPK is involved in arsenical stress response. Recently, we have identified SEK-1 MAPKK which functions upstream of PMK-1 (Tanaka-Hino et al., 2002). Consistent with this, PMK-1 activation in response to arsenical stimulus was lost in
sek-1 null mutants and the
sek-1 mutant animals were hypersensitive to sodium arsenite. The SEK-1 MAPKK regulates asymmetrical development of AWC neurons by acting downstream of UNC-43 CaMKII and NSY-1 MAPKKK (Sagasti et al., 2001;Tanaka-Hino et al., 2002). In
nsy-1 loss-of-function mutants arsenite-induced activation of PMK-1 partially decreased and the mutant animals showed partial sensitivity to sodium arsenite. However, the
unc-43 loss-of-function mutation had any effects on neither PMK-1 activation nor sensitivity induced by arsenic treatment. Taken together, these results suggest that the NSY-1-SEK-1-
p38 MAPK pathway regulates arsenical stress response in a manner independent of UNC-43. Furthermore, in this pathway other MAPKKK(s) may function upstream of SEK-1 MAPKK redundantly with NSY-1. Sagasti, A., Hisamoto, N., Hyodo, J., Tanaka-Hino, M., Matsumoto, K., Bargmann, C. I. The CaMKII UNC-43 activates the MAPKKK NSY-1 to excute a lateral signaling decision required for asymmetric olfactory neuron fates. Cell, 105: 221-232 (2001). Tanaka-Hino, M., Sagasti, A., Hisamoto, N., Kawasaki, M., Nakano, S., Ninomiya-Tsuji, J., Bargmann, C. I., Matsumoto, K. SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal asymmetric development in C. elegans . EMBO Rep., 3: 56-62 (2002).