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Substances that change alternative splice site selection

The recognition of alternative exons is frequently subjected to regulation. The utilization of an alternative exon depends on the cell type, the developmental stage, and/or the reception of cellular signals [reviewed in (Blaustein et al., 2007; Shin and Manley, 2004; Stamm, 2002)]. These changes can occur within one hour in animal systems (Daoud et al., 1999), and in most systems studied, these changes do not involve de novo protein synthesis (Stamm, 2002). Post-translational modifications of splicing factors, such as phosphorylation [reviewed in (Stamm, 2008)], glycosylation (Soulard et al., 1993), acetylation (Babic et al., 2004), or methylation (Rho et al., 2007), also play key roles in the regulation of splice-site selection.

The importance of proper splice site recognition is apparent from the growing number of human diseases that are recognized to be caused by the selection of incorrect splice sites (Faustino and Cooper, 2003; Stoilov et al., 2002). These diseases result from either mutations, as in the case of FTDP-17 and Duchenne’s muscular dystrophy or deregulation of the cellular splicing machinery, as exemplified by the numerous changes in alternative splicing seen in cancer (Venables, 2006). Alternative splicing has therefore rapidly emerged as a new drug target (Hagiwara, 2005), especially since protein isoforms generated by this process can have different pharmacological effects (Bracco and Kearsey, 2003). The unexpected alteration of alternative splice site selection may also explain side-effects that established drugs have in addition to their principal role.

The use of RNA-binding molecules as antibiotics, such as gentamicin, chloramphenicol, and tetracycline illustrates that drugs can be targeted against RNA and/or RNA binding proteins. High-throughput screens and testing of substances in model systems identified more substances that change splice site selection. The substances fall into several categories, including HDAC inhibitors, kinase and phosphatase inhibitors, as well as cAMP antagonist and agonists. The currently known substances are reviewed in (Sumanasekera et al., 2008) and updated on this page.

If you find a substance that is not listed here or if you are looking for a reporter gene to study such substances, please contact Chiranthani Sumanasekera at csuma1@uky.edu.

The mechanism of action of these drugs is poorly understood. We have tentatively classified them in the pdf below.

Click here for full table