3,3'-diindolylmethane induces activating transcription factor 3 (ATF3) via ATF4 in human colorectal cancer cells.
3,3'-diindolylmethane induces activating transcription factor 3 (ATF3) via ATF4 in human colorectal cancer cells.
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DOI：
10.1016/j.jnutbio.2012.03.016
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发表时间：
2013-04
期刊：
影响因子：
--
通讯作者：
Baek SJ
中科院分区：
文献类型：
--
作者：
Lee SH;Min KW;Zhang X;Baek SJ
3，3 ′-二吲哚甲烷（DIM）是十字花科蔬菜中吲哚-3-甲醇（I3 C）的主要体内缩合产物。尽管这些化合物在动物和体外癌症模型中具有广泛的抗肿瘤和促凋亡特性，但DIM调节的潜在细胞机制仅部分了解。转录激活因子3（ATF 3）是碱性区亮氨酸拉链（bZIP）家族的ATF/CREB亚家族的成员，并且已知其在人结直肠癌细胞中诱导凋亡。本研究旨在阐明DIM在人CRC细胞中诱导ATF 3的分子机制。DIM处理诱导细胞凋亡，并在蛋白和mRNA水平诱导ATF 3基因表达。DIM可提高ATF 3启动子的活性，其启动子的-84 ~+34区域含有ATF结合位点。ATF结合位点的缺失和点突变（−23至−16）消除了DIM对ATF 3启动子的激活，而过表达ATF 4则增强了ATF 3的反式激活。染色质免疫沉淀（ChIP）测定证实了ATF 4在ATF 3启动子中的结合。通过siRNA抑制ATF 4表达导致DIM诱导的ATF 3表达的阻遏。目前的研究表明，DIM通过ATF 4介导的途径刺激ATF 3表达，随后诱导人结直肠癌细胞凋亡。
A 3,3′-diindolylmethane (DIM) is a major in vivo condensation product of indole-3-carbinol (I3C), which are present in cruciferous vegetables. Although these compounds have been widely implicated in anti-tumorigenic and pro-apoptotic properties in animal as well as in vitro models of cancer, the underlying cellular mechanisms regulated by DIM are only partially understood. Activating transcription factor 3 (ATF3) is a member of the ATF/CREB subfamily of the basic-region leucine zipper (bZIP) family and has been known to induce apoptosis in human colorectal cancer cells. The present study was performed to elucidate the molecular mechanism of ATF3 induction by DIM in human CRC cells. The DIM treatment induced apoptosis and induced ATF3 gene expression at protein and mRNA levels. DIM increased ATF3 promoter activity and the region of −84 to +34 within ATF3 promoter was responsible for promoter activation by DIM. This region contained an ATF binding site. Deletion and point mutation of the ATF binding site (−23 to −16) abolished ATF3 promoter activation by DIM and overexpression of ATF4 enhanced ATF3 transactivation. Chromatin immunoprecipitation (ChIP) assay confirmed the binding of ATF4 in the ATF3 promoter. Inhibition of ATF4 expression by siRNA results in repression of DIM-induced ATF3 expression. The current study demonstrates that DIM stimulates ATF3 expression through ATF4-mediated pathway and subsequently induces apoptosis in human colorectal cancer cells.
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影响因子：
5.3
作者：
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通讯作者：
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影响因子：
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影响因子：
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作者：
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