首页> 外文期刊>The Journal of Nutritional Biochemistry >3,3'-Diindolylmethane induces activating transcription factor 3 (ATF3) via ATF4 in human colorectal cancer cells.
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3,3'-Diindolylmethane induces activating transcription factor 3 (ATF3) via ATF4 in human colorectal cancer cells.

机译:3,3'-Diindolylmethane通过人大肠癌细胞中的ATF4诱导激活转录因子3(ATF3)。

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摘要

3,3'-Diindolylmethane (DIM) is a major in vivo condensation product of indole-3-carbinol, which is present in cruciferous vegetables. Although these compounds have been widely implicated in antitumorigenic and proapoptotic 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/c-AMP response element-binding (CREB) subfamily of the basic-region leucine zipper family and has been known to induce apoptosis in human colorectal cancer (CRC) 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 messenger RNA 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 assay confirmed the binding of ATF4 in the ATF3 promoter. Inhibition of ATF4 expression by small interference RNA 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 CRC cells
机译:3,3'-Diindolylmethane(DIM)是吲哚-3-甲醇的主要体内缩合产物,该产物存在于十字花科蔬菜中。尽管这些化合物已广泛涉及动物的抗肿瘤和促凋亡特性以及体外癌症模型,但仅部分了解了由DIM调节的潜在细胞机制。激活转录因子3(ATF3)是基本区域亮氨酸拉链家族的ATF / c-AMP反应元件结合(CREB)亚家族的成员,并且已知在人大肠癌(CRC)细胞中诱导凋亡。进行本研究以阐明DIM在人CRC细胞中诱导ATF3的分子机制。 DIM处理在蛋白质和信使RNA水平诱导细胞凋亡并诱导ATF3基因表达。 DIM增加了ATF3启动子的活性,并且ATF3启动子中的--84至+34区域负责DIM的启动子激活。该区域包含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ATF3启动子的激活,而过表达ATF4增强了ATF3反式激活。染色质免疫沉淀试验证实了ATF3启动子中ATF4的结合。小干扰RNA抑制ATF4表达会抑制DIM诱导的ATF3表达。目前的研究表明,DIM通过ATF4介导的途径刺激ATF3表达,并随后诱导人CRC细胞凋亡

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