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The dynamic character of the BCL2 promoter i-motif provides a mechanism for modulation of gene expression by compounds that bind selectively to the alternative DNA hairpin structure.
- Source :
-
Journal of the American Chemical Society [J Am Chem Soc] 2014 Mar 19; Vol. 136 (11), pp. 4161-71. Date of Electronic Publication: 2014 Mar 07. - Publication Year :
- 2014
-
Abstract
- It is generally accepted that DNA predominantly exists in duplex form in cells. However, under torsional stress imposed by active transcription, DNA can assume nonduplex structures. The BCL2 promoter region forms two different secondary DNA structures on opposite strands called the G-quadruplex and the i-motif. The i-motif is a highly dynamic structure that exists in equilibrium with a flexible hairpin species. Here we identify a pregnanol derivative and a class of piperidine derivatives that differentially modulate gene expression by stabilizing either the i-motif or the flexible hairpin species. Stabilization of the i-motif structure results in significant upregulation of the BCL2 gene and associated protein expression; in contrast, stabilization of the flexible hairpin species lowers BCL2 levels. The BCL2 levels reduced by the hairpin-binding compound led to chemosensitization to etoposide in both in vitro and in vivo models. Furthermore, we show antagonism between the two classes of compounds in solution and in cells. For the first time, our results demonstrate the principle of small molecule targeting of i-motif structures in vitro and in vivo to modulate gene expression.
- Subjects :
- Animals
DNA chemistry
DNA genetics
Gene Expression Profiling
Humans
MCF-7 Cells
Mice
Mice, SCID
Nucleic Acid Conformation drug effects
Piperidines chemistry
Pregnanediol analogs & derivatives
Pregnanediol chemistry
Proto-Oncogene Proteins c-bcl-2 chemistry
Proto-Oncogene Proteins c-bcl-2 genetics
RNA, Messenger drug effects
RNA, Messenger genetics
RNA, Messenger metabolism
Structure-Activity Relationship
Tumor Cells, Cultured
DNA drug effects
Piperidines pharmacology
Pregnanediol pharmacology
Promoter Regions, Genetic genetics
Proto-Oncogene Proteins c-bcl-2 metabolism
Thermodynamics
Subjects
Details
- Language :
- English
- ISSN :
- 1520-5126
- Volume :
- 136
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of the American Chemical Society
- Publication Type :
- Academic Journal
- Accession number :
- 24559410
- Full Text :
- https://doi.org/10.1021/ja410934b