The tumor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phosphatase
The tumor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phosphatase
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DOI：
10.1002/j.1460-2075.1996.tb01017.x
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发表时间：
1996-11-15
期刊：
影响因子：
11.4
通讯作者：
Karin, M
中科院分区：
文献类型：
--
作者：
Cavigelli, M;Li, WW;Karin, M
三价砷（As3+）具有高度致癌性，但没有已知的致突变活性。因此，它很可能起到肿瘤启动子的作用。为了了解As3+促肿瘤活性的分子基础，我们研究了它对转录因子AP-1的影响，而转录因子AP-1的活性是由其他几种肿瘤启动子刺激的。我们发现As3+是AP-1转录活性的有效刺激物，是c-fos和c-jun基因表达的有效诱导剂，而As5+是有毒但不致癌的。As3+诱导c-jun和c-fos的转录与Jun激酶（JNKs）和p38/Mpk2的激活相关，后者磷酸化激活这些直接早期基因的转录因子。未观察到对ERK活性的影响。另一方面，As5+对JNK或p38/Mpk2活性的影响可以忽略不计。生化分析和共转染实验强烈表明，As3+刺激JNK活性的主要机制涉及抑制组成型双特异性JNK磷酸酶。这种磷酸酶活性似乎是在未受刺激的细胞中维持低基础JNK活性的原因，其抑制可能通过诱导原癌基因（如c-jun和c-fos）以及刺激AP-1活性来促进肿瘤。同样的磷酸酶也可能调节p38/Mpk2的活性。
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.