The tumor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phosphatase.
Trivalent arsenic (As3+) is highly carcinogenic, but devoid of known mutagenic activity. Therefore, it is likely to act as a tumor promoter. To understand the molecular basis for the tumor-promoting activity of As3+, we examined its effect on transcription factor AP-1, whose activity is stimulated by several other tumor promoters. We found that As3+, but not As5+, which is toxic but not carcinogenic, is a potent stimulator of AP-1 transcriptional activity and an efficient inducer of c-fos and c-jun gene expression. Induction of c-jun and c-fos transcription by As3+ correlates with activation of Jun kinases (JNKs) and p38/Mpk2, which phosphorylate transcription factors that activate these immediate early genes. No effect on ERK activity was observed. As5+, on the other hand, had a negligible effect on JNK or p38/Mpk2 activity. Biochemical analysis and co-transfection experiments strongly suggest that the primary mechanism by which As3+ stimulates JNK activity involves the inhibition of a constitutive dual-specificity JNK phosphatase. This phosphatase activity appears to be responsible for maintaining low basal JNK activity in non-stimulated cells and its inhibition may lead to tumor promotion through induction of proto-oncogenes such as c-jun and c-fos, and stimulation of AP-1 activity. The same phosphatase may also regulate p38/Mpk2 activity.
Cavigelli
M
M
Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla 92093-0636, USA.
Li
W W
WW
Lin
A
A
Su
B
B
Yoshioka
K
K
Karin
M
M
D018053:Arsenites / Q000494:pharmacology*; D015152:Blotting, Northern; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases
D018053:Arsenites; D002273:Carcinogens; D004268:DNA-Binding Proteins; D016755:Proto-Oncogene Proteins c-jun; D013438:Sulfhydryl Compounds; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; C015001:arsenite