Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 53, Issue 11, Pages 4390-4398Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm100445e
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Funding
- Natural Science Foundation of China [U0832005, 90813011, 20772159, 30801436]
- Science Foundation of Guangzhou [2009A1-E011-6]
- Ministry of Education of the People's Republic of China [200805581163]
- Guangdong Natural Science Foundation [8451008901000214]
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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.
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