DIFFERENTIAL ACTIVATION OF ERK, JNK SAPK AND P38/CSBP/RK MAP KINASE FAMILY MEMBERS DURING THE CELLULAR-RESPONSE TO ARSENITE/

Exposure of cells to either proliferative or stressful stimuli elicits a complex response involving one or more distinct phosphorylation cas cades culminating in the activation of multiple members of the mitogen -activated protein kinase (MAPK) family, including extracellular signa l regulated kinase (ERK), stress-activated c-Jun N-terminal kinase (JN K/SAPK), and p38/RK/CSBP protein kinase. While the pathways transducin g mitogenic stimuli to these kinases are relatively well established, the early signalling events leading to their activation in response to stress are poorly understood. In the present study, we examined ERK, JNK/SAPK, and p38 activation in cells treated with the sulfhydryl-reac tive agent sodium arsenite. Arsenite treatment potently activated both JNK/SAPK and p38, but only moderately activated ERK. Activation of al l three kinases was prevented by the free radical scavenger N-Acetyl-L -cysteine, suggesting that an oxidative signal initiates the responses . Suramin, a growth factor receptor poison, significantly inhibited ER K activation by arsenite, but had little effect on either JNK/SAPK or p38 activity. In contrast, suramin inhibited the activation of all thr ee kinases by snort wavelength ultraviolet light (UVC) irradiation. In addition, comparative studies with wild-type PC12 cells and PC12 cell s expressing a dominant negative Ras mutant allele indicated that arse nite activates ERK primarily through a Ras-dependent pathway(s), while activation of both JNK/SAPK and p38 occurs through a mechanism relati vely independent of Ras. These results suggest that JNK/SAPK and p38 m ay share common upstream regulators distinct from those involved in ER K activation.