Tpl2 is a key mediator of arsenite-induced signal transduction.
Tpl2 is a key mediator of arsenite-induced signal transduction.
复制标题
DOI：
10.1158/0008-5472.can-09-2316
复制
发表时间：
2009-10-15
期刊：
影响因子：
11.2
通讯作者：
Dong Z
中科院分区：
文献类型：
--
作者：
Lee KM;Lee KW;Bode AM;Lee HJ;Dong Z
亚砷酸盐是一种众所周知的人类致癌物，特别针对皮肤。肿瘤进展基因座2（Tpl 2）基因编码在各种癌细胞中过表达的丝氨酸/苏氨酸蛋白激酶。然而，Tpl 2在亚砷酸盐诱导的致癌作用中的相关性和潜在机制仍有待探索。我们表明，亚砷酸盐增加Tp 12激酶活性和磷酸化在小鼠表皮JB 6 P+细胞中的剂量和时间依赖性的方式。暴露于亚砷酸盐导致环氧合酶（考克斯）-2和前列腺素（PG）E2的显着诱导，炎症和肿瘤促进的重要介质。用Tp 12激酶抑制剂（TKI）或Tp 12短发夹RNA（shRNA）处理抑制由亚砷酸盐处理诱导的考克斯-2表达和PGE 2产生，表明Tp 12在亚砷酸盐诱导的致癌作用中是关键的。我们还发现亚砷酸盐诱导的细胞外信号调节激酶（ERK）或c-Jun NH 2-末端激酶（JNKs）的磷酸化被TKI或Tpl 2 shRNA显著抑制。使用ERK或JNKs的药理学抑制剂抑制亚砷酸盐诱导的ERK或JNKs信号传导基本上阻断了考克斯-2表达。此外，Tp 12的抑制降低了亚砷酸盐诱导的核因子κ B（NF-κB）和激活蛋白-1（AP-1）的启动子活性，表明NF-κB和AP-1是亚砷酸盐触发的Tp 12的下游转导物。我们的结果表明Tp 12在亚砷酸盐诱导的考克斯-2表达和PGE 2产生中起关键作用，并进一步阐明了Tp 12在亚砷酸盐激活JB 6 P+细胞中ERK/JNKs和NF-κB/AP-1的信号中的作用。
Arsenite is a well-known human carcinogen that especially targets skin. The tumor progression locus 2 (Tpl2) gene encodes a serine/threonine protein kinase that is overexpressed in various cancer cells. However, the relevance of Tpl2 in arsenite-induced carcinogenesis and the underlying mechanisms remain to be explored. We demonstrate that arsenite increased Tpl2 kinase activity and its phosphorylation in mouse epidermal JB6 P+ cells in a dose- and time-dependent manner. Exposure to arsenite resulted in a marked induction of cyclooxygenase (COX)-2 and prostaglandin (PG)E2, important mediators of inflammation and tumor promotion. Treatment with a Tpl2 kinase inhibitor (TKI) or Tpl2 short hairpin RNA (shRNA) suppressed COX-2 expression and PGE2 production induced by arsenite treatment, suggesting that Tpl2 is critical in arsenite-induced carcinogenesis. We also found that arsenite-induced phosphorylation of extracellular signal-regulated kinases (ERKs) or c-Jun NH2-terminal kinases (JNKs) was markedly suppressed by TKI or Tpl2 shRNA. Inhibition of arsenite-induced ERKs or JNKs signaling using a pharmacological inhibitor of ERKs or JNKs substantially blocked COX-2 expression. Furthermore, inhibition of Tpl2 reduced the arsenite-induced promoter activity of nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1), indicating that NF-κB and AP-1 are downstream transducers of arsenite-triggered Tpl2. Our results demonstrated that Tpl2 plays a key role in arsenite-induced COX-2 expression and PGE2 production and further elucidated the role of Tpl2 in arsenite signals that activate ERKs/JNKs and NF-κB/AP-1 in JB6 P+ cells.