G-quadruplex-binding benzo[a]phenoxazines down-regulate c-KIT expression in human gastric carcinoma cells.
G-quadruplex-binding benzo[a]phenoxazines down-regulate c-KIT expression in human gastric carcinoma cells.
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DOI：
10.1021/ja109474c
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发表时间：
2011-03-02
影响因子：
15
通讯作者：
Balasubramanian S
中科院分区：
文献类型：
--
作者：
McLuckie KI;Waller ZA;Sanders DA;Alves D;Rodriguez R;Dash J;McKenzie GJ;Venkitaraman AR;Balasubramanian S
对G-四链体核酸二级结构的结构和功能、它们的细胞功能以及它们作为治疗靶点的潜力有相当大的兴趣。G-四链体序列基序在基因启动子区域中普遍存在，并且已经假设G-四链体结构的形成与下游基因的转录状态相关。使用功能性细胞为基础的测定，我们已经确定了两个新的G-四链体配体，减少从G-四链体的c-KIT启动子驱动的荧光素酶报告的转录。我们进一步表明，在人胃癌细胞系中内源性c-KIT表达也在用这些分子治疗时降低。使用表面等离子体共振的生物物理分析表明，这些分子优先结合高亲和力的两个G-四链体序列中的一个在c-KIT启动子的双链DNA。这项工作突出了基于细胞的报告基因检测的实用性，以确定新的G-四链体结合分子，调节转录，并确定苯并[a]吩恶嗪衍生物作为潜在的抗肿瘤药物。
There is considerable interest in the structure and function of G-quadruplex nucleic acid secondary structures, their cellular functions, and their potential as therapeutic targets. G-Quadruplex sequence motifs are prevalent in gene promoter regions and it has been hypothesized that G-quadruplex structure formation is associated with the transcriptional status of the downstream gene. Using a functional cell-based assay, we have identified two novel G-quadruplex ligands that reduce the transcription of a luciferase reporter driven from the G-quadruplex-containing c-KIT promoter. We have further shown that endogenous c-KIT expression in a human gastric carcinoma cell line is also reduced on treatment with these molecules. Biophysical analysis using surface plasmon resonance has shown that these molecules preferentially bind with high affinity to one of the two G-quadruplex sequences in the c-KIT promoter over double-stranded DNA. This work highlights the utility of cell-based reporter assays to identify new G-quadruplex binding molecules that modulate transcription and identifies benzo[a]phenoxazine derivatives as potential antitumor agents.
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TrisubStttestated的异丙恶唑作为新的G四链体结合配体：C-KIT癌基因表达的小分子调节。
影响因子：
15
作者：
Bejugam, Mallesham;Sewitz, Sven;Shirude, Pravin S.;Rodriguez, Raphael;Shahid, Ramla;Balasubramanian, Shankar
通讯作者：
Balasubramanian, Shankar
影响因子：
11.4
作者：
Huang, S;Jean, D;Bar-Eli, M
通讯作者：
Bar-Eli, M
影响因子：
6.7
作者：
Choi, Jeong June;Park, Bo-Kyung;Jin, Mirim
通讯作者：
Jin, Mirim
干细胞因子/C-KIT受体途径增强了胰腺癌细胞的增殖和侵袭。
影响因子：
37.3
作者：
通讯作者：
--
影响因子：
11.2
作者：
McIntyre, A;Summersgill, B;Shipley, J
通讯作者：
Shipley, J