Activating transcription factor 2 (ATF2) controls tolfenamic acid-induced ATF3 expression via MAP kinase pathways.
Activating transcription factor 2 (ATF2) controls tolfenamic acid-induced ATF3 expression via MAP kinase pathways.
复制标题
DOI：
10.1038/onc.2010.251
复制
发表时间：
2010-09-16
期刊：
影响因子：
8
通讯作者：
Baek, S. J.
中科院分区：
文献类型：
--
作者：
Lee, S-H;Bahn, J. H.;Whitlock, N. C.;Baek, S. J.
托芬那酸(TA)是一种非甾体抗炎药，在动物和体外肿瘤模型中具有抗肿瘤和促细胞凋亡的作用。然而，TA发挥作用的潜在细胞机制还只有部分了解。激活转录因子3(ATF3)是碱性区域亮氨酸拉链家族中ATF/CREB亚家族的成员，被认为是结直肠癌细胞中的一种肿瘤抑制因子。本研究旨在观察ATF3是否介导TA诱导的细胞凋亡，并阐明TA诱导ATF3转录的分子机制。TA处理和ATF3的异位表达增加了细胞的凋亡率，而ATF3的敲除则显着抑制了TA激活的细胞凋亡。TA处理还诱导了ATF3启动子的活性。ATF3启动子中预测的ATF/C/EBP结合位点的内部缺失和点突变可阻断TA激活的荧光素酶。ATF2过表达导致ATF3启动子活性显著增加，凝胶迁移率改变分析表明该区域是ATF2结合的核心序列。TA处理后，ATF2的磷酸化水平增加，ATF3的转录水平也随之增加。ATF2基因敲除可抑制TA诱导的ATF3表达。我们进一步提供了TA导致磷酸化p38MAPK、JNK和ERK水平增加的证据。使用选择性抑制剂和显性负结构抑制这些途径可以改善TA诱导的ATF3表达和启动子活性。目前的研究表明，TA可刺激ATF3的表达，进而诱导细胞凋亡。这些通路是通过ATF2的磷酸化介导的，而ATF2是由p38MAPK、JNK和ERK依赖的通路介导的。
Tolfenamic acid (TA) is a non-steroidal anti-inflammatory drug associated with anti-tumorigenic and pro-apoptotic properties in animal and in vitro models of cancer. However, the underlying cellular mechanisms by which TA exerts its effects are only partially understood. Activating transcription factor 3 (ATF3) is a member of the ATF/CREB subfamily of the basic region-leucine zipper family and has been known as a tumor suppressor in human colorectal cancer cells. The present study was performed to observe whether ATF3 mediates TA-induced apoptosis and to elucidate the molecular mechanism of ATF3 transcription induced by TA. TA treatment and ectopic expression of ATF3 increased apoptosis whereas knockdown of ATF3 resulted in significant repression of TA-activated apoptosis. The TA treatment also induced ATF3 promoter activity. Internal deletion and point mutation of the predicted ATF/C/EBP binding site in ATF3 promoter abolished luciferase activation by TA. Overexpression of ATF2 resulted in significant increase of ATF3 promoter activity, and electrophoretic mobility shift assay identified this region as a core sequence to which ATF2 binds. TA treatment resulted in an increase of ATF2 phosphorylation, which was followed by a subsequent increase of ATF3 transcription. Knockdown of ATF2 abolished TA-induced ATF3 expression. We further provide evidence that TA leads to increases of phospho-p38 MAPK, JNK, and ERK levels. Inhibition of these pathways using selective inhibitors and dominant negative constructs ameliorated TA-induced ATF3 expression and promoter activities. The current study demonstrates that TA stimulates ATF3 expression and subsequently induces apoptosis. These pathways are mediated through phosphorylation of ATF2, which is mediated by p38 MAPK, JNK, and ERK-dependent pathways.
登录
查看更多内容
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
5.7
作者：
Lee SH;Bahn JH;Choi CK;Whitlock NC;English AE;Safe S;Baek SJ
通讯作者：
Baek SJ
影响因子：
3.6
作者：
Chen, HH;Wang, DL
通讯作者：
Wang, DL
影响因子：
10.5
作者：
HAI, T;LIU, F;GREEN, MR
通讯作者：
GREEN, MR
影响因子：
4.8
作者：
Huang, Xiangwei;Li, Xia;Guo, Bin
通讯作者：
Guo, Bin