Turning off transcription of the bcl-2 gene by stabilizing the bcl-2 promoter quadruplex with quindoline derivatives.
Human bcl-2 gene is an apoptosis-related oncogene containing a GC-rich sequence which is located upstream from P1 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.
Wang
Xiao-Dong
XD
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Ou
Tian-Miao
TM
Lu
Yu-Jing
YJ
Li
Zeng
Z
Xu
Zheng
Z
Xi
Chen
C
Tan
Jia-Heng
JH
Huang
Shi-Liang
SL
An
Lin-Kun
LK
Li
Ding
D
Gu
Lian-Quan
LQ
Huang
Zhi-Shu
ZS
D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D054856:G-Quadruplexes / Q000187:drug effects*; D019254:Genes, bcl-2 / Q000235:genetics*; D018922:HL-60 Cells; D006801:Humans; D006878:Hydroxides / Q000737:chemistry; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D013816:Thermodynamics; D014158:Transcription, Genetic / Q000187:drug effects*
D000470:Alkaloids; D006878:Hydroxides; D007211:Indoles; D008024:Ligands; D011804:Quinolines; C016712:quindoline; C031356:hydroxide ion