Journal of Biological Chemistry
Volume 283, Issue 48, 28 November 2008, Pages 33147-33154
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RNA: Processing and Catalysis
The Biflavonoid Isoginkgetin Is a General Inhibitor of Pre-mRNA Splicing*

https://doi.org/10.1074/jbc.M805556200Get rights and content
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Membrane-permeable compounds that reversibly inhibit a particular step in gene expression are highly useful tools for cell biological and biochemical/structural studies. In comparison with other gene expression steps where multiple small molecule effectors are available, very few compounds have been described that act as general inhibitors of pre-mRNA splicing. Here we report construction and validation of a set of mammalian cell lines suitable for the identification of small molecule inhibitors of pre-mRNA splicing. Using these cell lines, we identified the natural product isoginkgetin as a general inhibitor of both the major and minor spliceosomes. Isoginkgetin inhibits splicing both in vivo and in vitro at similar micromolar concentrations. It appears to do so by preventing stable recruitment of the U4/U5/U6 tri-small nuclear ribonucleoprotein, resulting in accumulation of the prespliceosomal A complex. Like two other recently reported general pre-mRNA splicing inhibitors, isoginkgetin has been previously described as an anti-tumor agent. Our results suggest that splicing inhibition is the mechanistic basis of the anti-tumor activity of isoginkgetin. Thus, pre-mRNA splicing inhibitors may represent a novel avenue for development of new anti-cancer agents.

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*

This work was supported, in whole or in part, by National Institutes of Health Grant R01-GM35007 (to M. J. M.) and the National Institutes of Health, NCI, Initiative for Chemical Genetics, under Contract N01-CO-12400. This work was performed with the assistance of the Chemical Biology Platform of the Broad Institute of Harvard and MIT. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1.