Proposed model indicating the different roles of candidate activators in the activation of phase 2 detoxification gene expression . TIR-1, NSY-1, THOC-2, UFD-2, K04G7.11, APB-3 and CSN-2 participate in the activation of phase 2 detoxification gene expression and oxidative stress resistance. In C. elegans the SKN-1 transcription factor is essential for phase 2 detoxification gene expression and oxidative stress resistance. Levels of SKN-1 in intestinal nuclei are normally low due to inhibitory phosphorylation by (a) GSK-3 (serine 393)  and (b) insulin-regulated kinases  and (c) interaction with WDR-23, which inhibits DNA binding ,. Oxidative stress increases the phosphorylation of the PMK-1 MAPK. Active PMK-1 phosphorylates SKN-1, increasing levels of SKN-1 in intestinal nuclei, phase 2 gene expression and oxidative stress resistance . Our data suggest that TIR-1 and NSY-1 are important for arsenite-induced activation of PMK-1 but that THOC-2 and UFD-2 act downstream of PMK-1 to promote SKN-1 activity by unidentified mechanism(s). Intriguingly, our data suggest that several candidates identified by our screen, including APB-3, CSN-2 and K04G7.11, may be dispensable for the expression of other phase 2 detoxification genes but act to increase expression of gcs-1 via unidentified mechanisms downstream or independently from PMK-1 and SKN-1. We suggest that the increased nuclear levels of SKN-1 in apb-3, csn-2 and K04G7.11 RNAi-treated animals, which have lower arsenite-induced gcs-1 expression (Figure 2B and 6C), could indicate that glutathione contributes to a feedback mechanism to inhibit SKN-1 (as indicated by ?). ROS, reactive oxygen species.