2007年9月
Splicing factor SF3b as a target of the antitumor natural product pladienolide
NATURE CHEMICAL BIOLOGY
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- 巻
- 3
- 号
- 9
- 開始ページ
- 570
- 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
- 10.1038/nchembio.2007.16
- 出版者・発行元
- NATURE PUBLISHING GROUP
Pladienolide is a naturally occurring antitumor macrolide that was discovered by using a cell-based reporter gene expression assay controlled by the human vascular endothelial growth factor promoter(1,2). Despite the unique mechanisms of action(3) and prominent antitumor activities of pladienolides B and D in diverse in vitro and in vivo systems(3), their target protein has remained unclear. We used H-3-labeled, fluorescence-tagged and photoaffinity/biotin (PB)-tagged 'chemical probes' to identify a 140-kDa protein in splicing factor SF3b as the binding target of pladienolide. Immunoblotting of an enhanced green fluorescent protein fusion protein of SF3b subunit 3 (SAP130) revealed direct interaction between the PB probe and SAP130. The binding affinities of pladienolide derivatives to the SF3b complex were highly correlated with their inhibitory activities against reporter gene expression and cell proliferation. Furthermore, pladienolide B impaired in vivo splicing in a dose-dependent manner. Our results demonstrate that the SF3b complex is a pharmacologically relevant protein target of pladienolide and suggest that this splicing factor is a potential antitumor drug target.
- リンク情報
- ID情報
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- DOI : 10.1038/nchembio.2007.16
- ISSN : 1552-4450
- PubMed ID : 17643112
- Web of Science ID : WOS:000248968000015