期刊
BIOCHEMISTRY
卷 48, 期 31, 页码 7392-7398出版社
AMER CHEMICAL SOC
DOI: 10.1021/bi9006836
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资金
- Korea Science and Engineering Foundation (KOSEF)
- Korea government (MEST) [R01-2008-000-20771-0]
- National Research Foundation of Korea [R01-2008-000-20771-0, 과C6A2103] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Actinomycin D (ActD) is a natural antibiotic that inhibits the transcription of genes by interacting with a GC-rich duplex, a single-stranded or hairpin form of DNA, and then interfering with the action of RNA polymerase. In this study, we identified a novel molecular mechanism of anticancer activity of ActD as all oncogenic c-Myc promoter G-quadruplex binder. ActD, selectively inhibits the elongation of oligonucleotides containing c-Myc promoter G-quadruplex sequence in PCR-stop assays. UV-vis spectroscopic and circular dichroism studies suggest that ActD interacts with c-Myc promoter G-quadruplex via a surface end stacking interaction, inducing a mixed-type conformation of the G-quadruplex. ActD selectively inhibits the cellular growth and synthesis of c-Myc m RNA in Ramos cells having the NHEIII1 region in the translocated c-Myc gene. In addition, the results of promoter assays using two kinds of NHEIII1 region Mutants and wild-type constructs strongly Support the idea that binding of ActD with G-quadruplex formed in the promoter region results in the reporter gene being turned off. Our study reveals a novel mechanism underlying the anticancer activity of ActD, whereby ActD, interacts with oncogenic promoter G-quadruplex DNA to repress gene expression.
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