A JNK1/AP-1-dependent, COX-2 induction is implicated in 12-O-tetradecanoylphorbol-13-acetate-induced cell transformation through regulating cell cycle progression.
A JNK1/AP-1-dependent, COX-2 induction is implicated in 12-O-tetradecanoylphorbol-13-acetate-induced cell transformation through regulating cell cycle progression.
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JNK1/AP-1 依赖性 COX-2 诱导通过调节细胞周期进程参与 12-O-tetradecanoylphorbol-13-acetate 诱导的细胞转化。
DOI：
10.1158/1541-7786.mcr-07-0181
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Huang,Chuanshu
中科院分区：
文献类型：
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作者：
Zhang,Dongyun;Li,Jingxia;Song,Lun;Ouyang,Weiming;Gao,Jimin;Huang,Chuanshu
环氧合酶-2（Cyclooxygenase-2，考克斯-2）是12-O-十四烷酰佛波醇-13-乙酸酯（12-O-tetradecanoylphorbol-13-acetate，TPA）诱导的早期反应基因产物之一。然而，考克斯-2在TPA诱导的细胞转化中的相关性及其机制仍有待进一步研究。最初，我们验证了TPA处理后小鼠胚胎成纤维细胞（MEF）和小鼠表皮细胞Cl 41中的考克斯-2诱导。更重要的是，在MEFs或Cl 41细胞中引入考克斯-2小干扰RNA抑制TPA处理引起的细胞转化。这种抑制作用可被人全长考克斯-2的过表达所逆转，表明考克斯-2至少是TPA诱导的细胞转化中涉及的关键分子之一。我们进一步发现，TPA促进的细胞周期进程被考克斯-2小干扰RNA部分抑制，表明考克斯-2也参与TPA相关的细胞周期进程。对上游信号通路的研究表明，c-Jun-NH 2-kinase 1（JNK 1）而非JNK 2在考克斯-2的诱导中起重要作用，因为JNK 1基因的敲除而非JNK 2基因的敲除明显损害了考克斯-2的诱导。此外，通过过度表达c-Jun的显性失活突变体或MKK 4和MKK 7来抑制c-Jun/激活蛋白1途径或JNK/c-Jun途径，导致考克斯-2诱导的损害，表明JNK 1/c-Jun/激活蛋白1途径参与TPA相关的考克斯-2诱导。而IKK/p65核因子-κB通路则不受影响，因为IKKα、IKKβ或p65基因敲除后，尽管TPA激活了核因子-κB，但对考克斯-2的诱导无影响。此外，TPA促进的细胞周期进程被发现受损JNK 1缺陷，但不是在JNK 2缺陷，MEFs。我们的研究结果表明，JNK 1相关的考克斯-2诱导涉及TPA相关的细胞转化和细胞周期进程。(Mol Cancer Res 2008;6（1）：165-74）
Cyclooxygenase-2 (COX-2) is reported to be one of the early-response gene products induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). However, the relevance of COX-2 in TPA-induced cell transformation and the underlying mechanisms remains to be explored. Initially, we verified COX-2 induction after TPA treatment in mouse embryonic fibroblasts (MEF) and mouse epidermal cells Cl 41. More importantly, introduction of COX-2 small interfering RNA in MEFs or Cl 41 cells suppressed the cell transformation caused by TPA treatment. This inhibition could be reversed by overexpression of human full-length COX-2, indicating that COX-2 is at least one of the critical molecules involved in TPA-induced cell transformation. We further showed that TPA-promoted cell cycle progression was partially suppressed by COX-2 small interfering RNA, indicating that COX-2 also participated in TPA-associated cell cycle progression. Investigation of the upstream signaling pathways revealed that c-Jun-NH2-kinase 1 (JNK1), but not JNK2, played important roles in COX-2 induction, because knockout ofJNK1gene rather thanJNK2gene markedly impaired COX-2 induction. Furthermore, inhibition of c-Jun/activator protein 1 pathway or JNKs/c-Jun pathway by overexpression of dominant negative mutants of c-Jun, or MKK4 and MKK7 together, resulted in impairment of COX-2 induction, suggesting that JNK1/c-Jun/activator protein 1 pathway is involved in TPA-associated COX-2 induction. In contrast, IKK/p65 nuclear factor-κB pathway was not implicated because knockout of IKKα, IKKβ, orp65gene did not affect COX-2 induction although nuclear factor-κB was activated by TPA. In addition, the TPA-promoted cell cycle progression was found impaired in JNK1-deficient, but not in JNK2-deficient, MEFs. Our results show that JNK1-associated COX-2 induction is implicated in TPA-associated cell transformation and cell cycle progression. (Mol Cancer Res 2008;6(1):165–74)