Turning off Transcription of the bcl-2 Gene by Stabilizing the bcl-2 Promoter Quadruplex with Quindoline Derivatives
Turning off Transcription of the bcl-2 Gene by Stabilizing the bcl-2 Promoter Quadruplex with Quindoline Derivatives
复制标题
通过使用喹啉衍生物稳定 bcl-2 启动子四联体来关闭 bcl-2 基因的转录
DOI：
10.1021/jm100445e
复制
发表时间：
2010-06-10
影响因子：
7.3
通讯作者：
Huang, Zhi-Shu
中科院分区：
文献类型：
--
作者：
Wang, Xiao-Dong;Ou, Tian-Miao;Huang, Zhi-Shu
人bcl-2基因是一种与乳腺癌相关的癌基因，它含有一段富含GC的序列，位于PI启动子上游，具有形成G-四链体的潜力。然而，四链体的调节作用及其配体对bcl-2的影响尚未阐明。在这里，我们证明了G-四链体结构被破坏时，部分突变的G A，导致在bcl-2启动子的基础转录活性增加2倍。本课题组开发的高活性G-四链体配体喹多啉衍生物能显著抑制bcl-2的转录激活，但对突变bcl-2的转录影响较小。这些结果为bcl-2基因启动子区形成的G-四链体结构作为转录抑制元件发挥作用提供了直接证据，G-四链体特异性配体通过稳定四链体结构调控bcl-2基因的转录。结果进一步表明喹多啉衍生物可诱导HL-60肿瘤细胞凋亡。
Human bcl-2 gene is an apoptosis-related oncogene containing a GC-rich sequence which is located upstream from PI promoter and has the potential to form G-quadruplex structures. However, the regulatory role of the quadruplex and the effect of its ligands on bcl-2 have not been clarified. Here, we demonstrated that the G-quadruplex structure was disrupted when partial mutation of G A was made, resulting in a 2-fold increase in basal transcriptional activity of bcl-2 promoter. Quindoline derivatives, the highly active G-quadruplex ligands developed by our group, could significantly suppress bcl-2 transcriptional activation but had less effect on mutated bcl-2 transcription. These results provided direct evidence that G-quadruplex structure formed in bcl-2 promoter region could function as a transcriptional repressor element, and G-quadruplex specific ligands could regulate the transcription of bcl-2 through stabilization of quadruplex structure. The results further indicated that quindoline derivatives could induce apoptosis of HL-60 tumor cells.