Polyoma enhancer activator 3, an Ets transcription factor, mediates the induction of cyclooxygenase-2 by nitric oxide in colorectal cancer cells
Polyoma enhancer activator 3, an Ets transcription factor, mediates the induction of cyclooxygenase-2 by nitric oxide in colorectal cancer cells
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DOI：
10.1074/jbc.m308136200
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发表时间：
2004-04-30
影响因子：
4.8
通讯作者：
Phang, JM
中科院分区：
文献类型：
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作者：
Liu, YM;Borchert, GL;Phang, JM
大量证据支持环氧化酶-2（考克斯-2）在结直肠癌中的作用。一氧化氮（NO），一种促炎信号传导因子，可调节考克斯-2表达和活性，从而将高度炎症状态与癌症易感性联系起来。以前我们发现NO诱导考克斯-2的表达。虽然NO也激活了β-连环蛋白。T细胞因子/淋巴细胞增强因子转录途径，该途径与考克斯-2表达之间的直接因果关系尚未得到证实。在本研究中，我们着重于NO诱导的转录活性，并阐明其在考克斯-2表达中的作用。NO供体刺激过氧化物酶体增殖物激活受体-δ和c-myc的表达，这两个基因的下游β-连环蛋白。它们还诱导多瘤增强子激活物3（PEA 3）的表达并增加其DNA结合活性。为了确定PEA 3对β-连环蛋白诱导的考克斯-2的作用，我们用β-连环蛋白转染RKO细胞，发现β-连环蛋白增加PEA 3表达。此外，与年轻成年小鼠结肠细胞（Apc（+/+））相比，永生小鼠结肠上皮细胞（Apc（Min/+））中存在更高的PEA 3。荧光素酶报告基因分析表明，尽管几种转录因子/共激活因子单独或协同作用，诱导考克斯-2启动子活性，PEA 3是最有效的之一。有趣的是，来自NO供体或从转染的诱导型一氧化氮合酶内源性产生的NO增加PEA 3/p300诱导的考克斯-2启动子活性。我们还发现ETS位点（-75/-72）和NF-IL 6位点负责PEA 3、PEA 3/p300和NO诱导的考克斯-2活性。综上所述，我们的结果表明NO通过β-catenin信号刺激PEA 3增加考克斯-2活性。此外，NO增强了PEA 3和CBP/p300之间的协同作用。
Abundant evidence supports the role of cyclooxygenase-2 (COX-2) in colorectal cancer. Nitric oxide ( NO), a pro-inflammatory signaling factor, may regulate COX-2 expression and activity thereby linking hyper-inflammatory states to cancer susceptibility. Previously we showed that NO induced COX-2 expression. Although NO also activated the beta-catenin . T-cell factor/lymphocyte enhancing factor transcriptional pathway, a direct causal link between this pathway and COX-2 expression was not demonstrated. In this current study, we focused on NO-induced transcriptional activity and elucidated its role in COX-2 expression. NO donors stimulated the expression of peroxisome proliferator-activated receptor-delta and c-myc, both downstream genes of beta-catenin. They also induced the expression of polyoma enhancer activator 3 (PEA3) and increased its DNA-binding activity. To establish a role for PEA3 to beta-catenin-induced COX-2, we transfected RKO cells with beta-catenin and found that beta-catenin increased PEA3 expression. Also, there was higher PEA3 in immortal mouse colon epithelium cells (Apc(Min/+)) compared with young adult mouse colon cells (Apc(+/+)). Luciferase reporter assays revealed that, although several transcription factors/coactivator, acting alone or in synergistic combination, induced COX-2 promoter activity, PEA3 was one of the most potent. Interestingly, NO from NO donors or generated endogenously from transfected inducible nitric-oxide synthase, increased PEA3/p300-induced COX-2 promoter activity. We also found that an ETS site (-75/ - 72) and the NF-IL6 site were responsible for COX-2 activity induced by PEA3, PEA3/p300, and NO. Taken together, our results demonstrated that NO through beta-catenin signaling stimulated PEA3 to increase COX-2 activity. In addition, NO augmented the synergistic interaction between PEA3 and CBP/p300.