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 cascades culminating in the activation of multiple members of the mitogen-activated protein kinase (MAPK) family, including extracellular signal regulated kinase (ERK), stress-activated c-Jun N-terminal kinase (JNK/SAPK), and p38/RK/CSBP protein kinase. While the pathways transducing 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-reactive agent sodium arsenite. Arsenite treatment potently activated both JNK/SAPK and p38, but only moderately activated ERK. Activation of all 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 ERK activation by arsenite, but had little effect on either JNK/SAPK or p38 activity. In contrast, suramin inhibited the activation of all three kinases by short wavelength ultraviolet light (UVC) irradiation. In addition, comparative studies with wild-type PC12 cells and PC12 cells expressing a dominant negative Ras mutant allele indicated that arsenite activates ERK primarily through a Ras-dependent pathway(s), while activation of both JNK/SAPK and p38 occurs through a mechanism relatively independent of Ras. These results suggest that JNK/SAPK and p38 may share common upstream regulators distinct from those involved in ERK activation.
Gene Expression and Aging Section, National Institute on Aging, Baltimore, Maryland 21224, USA.
Y
Y
Liu
K Z
KZ
Guyton
M
M
Gorospe
Q
Q
Xu
J C
JC
Lee
N J
NJ
Holbrook
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D018053:Arsenites / Q000494:pharmacology*; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts; D016166:Free Radical Scavengers / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D016716:PC12 Cells; D051381:Rats; D017670:Sodium Compounds / Q000494:pharmacology*; D013498:Suramin / Q000494:pharmacology; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins / Q000502:physiology
D018053:Arsenites; D016166:Free Radical Scavengers; D017670:Sodium Compounds; C017947:sodium arsenite; D013498:Suramin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins; D000111:Acetylcysteine