2005年11月
Synthetic pyrrole-imidazole polyamide inhibits expression of the human transforming growth factor-beta 1 gene
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
- 巻
- 315
- 号
- 2
- 開始ページ
- 571
- 終了ページ
- 575
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1124/jpet.105.089086
- 出版者・発行元
- AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
Pyrrole-imidazole (Py-Im) polyamides can bind to the predetermined base pairs in the minor groove of double-helical DNA with high affinity. These synthetic small molecules can interfere with transcription factor-DNA interaction and inhibit or activate the transcription of corresponding genes. In the present study, we designed and synthesized a Py-Im polyamide to target -545 to -539 base pairs of human transforming growth factor- beta 1 (hTGF-beta 1) promoter adjacent to the fat-specific element 2 (FSE2) to inhibit the expression of the gene. Gel mobility shift assay showed that the synthetic Py-Im polyamide binds to its corresponding double-strand oligonucleotides, whereas the mismatch polyamides did not bind. Fluorescein isothiocyanatelabeled Py-Im polyamide was detected in the nuclei of human vascular smooth muscle cells (VSMCs) after 2- to 48-h incubation. Py-Im polyamide significantly decreased the promoter activity of hTGF-beta 1 determined by in vitro transcription experiments and luciferase assay. In cultured human VSMCs, Py-Im polyamide targeting hTGF-beta 1 promoter significantly inhibited expressions of hTGF-beta 1 mRNA and protein. These results indicate that the synthetic Py-Im polyamide designed to bind hTGF-beta 1 promoter inhibited hTGF-beta 1 gene and protein expression successfully. This novel agent will be used for the TGF-beta-related diseases as a gene therapy.
- リンク情報
- ID情報
-
- DOI : 10.1124/jpet.105.089086
- ISSN : 0022-3565
- PubMed ID : 16120815
- Web of Science ID : WOS:000232681300012