title: Turning off transcription of the bcl-2 gene by stabilizing the bcl-2 promoter quadruplex with quindoline derivatives.
abstract: 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.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Wang
authors.forename: Tian-Miao
authors.initials: TM
authors.lastname: Ou
authors.forename: Yu-Jing
authors.initials: YJ
authors.lastname: Lu
authors.forename: Zeng
authors.initials: Z
authors.lastname: Li
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xu
authors.forename: Chen
authors.initials: C
authors.lastname: Xi
authors.forename: Jia-Heng
authors.initials: JH
authors.lastname: Tan
authors.forename: Shi-Liang
authors.initials: SL
authors.lastname: Huang
authors.forename: Lin-Kun
authors.initials: LK
authors.lastname: An
authors.forename: Ding
authors.initials: D
authors.lastname: Li
authors.forename: Lian-Quan
authors.initials: LQ
authors.lastname: Gu
authors.forename: Zhi-Shu
authors.initials: ZS
authors.lastname: Huang
mesh_terms: 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*
chemical_list: D000470:Alkaloids; D006878:Hydroxides; D007211:Indoles; D008024:Ligands; D011804:Quinolines; C016712:quindoline; C031356:hydroxide ion