Substances that change alternative splice site selection

The recognition of alternative exons is frequently subjected to regulation. The utilisation 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 recognised 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.

EURASNET groups (for example, Stefan Stamm, Jamal Tazi, Angus Lamond) are involved in the discovery of substances which can alter alternative splicing.

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 (in press)) 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.

  Small Molecule Name Mechanism Regulated Exon Structure Reference

Histone Deacetylase (HDAC) Inhibitors

1 sodium butyrate HDAC inhibitor SMN2 exon 7  Image of the structure Opens in a new window - link to the reference on PubMed
2 valproic acid HDAC
inhibitor
SMN2 exon 7  Image of the structure Opens in a new window - link to the reference on PubMed
3 sodium 4-phenylbutyrate HDAC
inhibitor
SMN2 exon 7  Image of the structure Opens in a new window - link to the reference on PubMed
4 N-hydroxyl-7-(4- (dimethylamino)benzoyl)
aminoheptanamide (M344)
HDAC
inhibitor
SMN2 exon 7  Image of the structure Opens in a new window - link to the reference on PubMed
5 suberoylanilide hydroxamic acid (SAHA) HDAC
inhibitor
SMN2 exon 7  Image of the structure Opens in a new window - link to the reference on PubMed
           

Kinase Inhibitors

6 aclarubicin  Topo I  SMN2 exon 7  Image of the structure Opens in a new window - link to the reference on PubMed
7 camptothecin Topo I CASP-2 exon 9  Image of the structure Opens in a new window - link to the reference on PubMed
8 6-N-formylamino-12,13- dihydro-1,11-dihydroxy-13- (β-D-glucopyranosyl) 5H-indolo  [2,3-a]pyrrolo [3,4-c]carbazole-5,7 (6H)-dione (NB-506) Topo I Bcl-X  and
CD 44
 Image of the structure Opens in a new window - link to the reference on PubMed
9 isodiospyrin Topo I Not defined (ND)  Image of the structure Opens in a new window - link to the reference on PubMed
10 (Z)-1-(3-ethyl-5-methoxy-2, 3-dihydrobenzothiazol- 2-ylidene) propan-2-one (TG003) CLK kinases Clk1/sty exon 2 and E1A  Image of the structure Opens in a new window - link to the reference on PubMed
11 lithium chloride GSK3 Tau
exon 10
 LiC1 Opens in a new window - link to the reference on PubMed
12 N-(4-methoxybenzyl)-N’- (5-nitro-1,3-thiazol-2-yl) urea (AR-A014418) GSK3 Tau
 exon 10
 Image of the structure Opens in a new window - link to the reference on PubMed Opens in a new window - link to the reference on PubMed
           

Phosphatase Inhibitors

13 sodium orthovanadate non-specific inhibitor SMN2
exon 7
 Na3VO4  Opens in a new window - link to the reference on PubMed
14 N-(hexanoyl)sphingosine (C6-ceramide) PP1 regulation Bcl-X and
 CASP-9
 Image of the structure Opens in a new window - link to the reference on PubMed
15 tautomycin PP1 inhibition SMN2
exon 7 and multiple other exons
 Image of the structure Opens in a new window - link to the reference on PubMed
16 cantharidin PP1 inhibition SMN2
      exon 7
 Image of the structure Opens in a new window - link to the reference on PubMed
           

cAMP Pathway

17 rac-2-[4-(1-oxo-2- isoindolinyl) phenyl]propionic acid (indoprofen) phospho-diesterase inhibitor?  SMN2   Opens in a new window - link to the reference on PubMed
18 2-(tert-butylamino)-1- (4-hydroxy-3- hydroxymethylphenyl) ethanol sulfate (salbutamol) adrenergic antagonist SMN2
exon 7
 Image of the structure Opens in a new window - link to the reference on PubMed
           

SR-Protein-Protein Interactions

19 10-chloro-2,6- dimethyl-2H- pyrido[3’,4’:4,5] pyrrolo[2,3-g]isoquinoline (IDC16)  SR-protein interaction HIV-1 mRNA  Image of the structure Opens in a new window - link to the reference on PubMed Opens in a new window - link to the reference on PubMed
           

Coupling of Transcription and Splicing

20 dexamethazone coupling of transcription and splicing coupling of transcription and spclicing Insulin receptor mRNA  Image of the structure Opens in a new window - link to the reference on PubMed
21 dihydroepiandrosterone (DHEA) coupling of transcription and splicing  Stress axis-regulated (STREX) exon  Image of the structure Opens in a new window - link to the reference on PubMed
22 steroid hormones    ND Reporter CD44 mini-gene   Opens in a new window - link to the reference on PubMed
           

Ion Channels and Electrochemical Gradients

23 5-(N-ethyl-N-isopropyl) amiloride (EIPA) change in ion gradient SMN2  Image of the structure Opens in a new window - link to the reference on PubMed
24 glutamate change in ion gradient Ania-6 mRNA   Opens in a new window - link to the reference on PubMed Opens in a new window - link to the reference on PubMed
           

Unknown Role

25 hydroxyurea ND SMN2
exon 7
 Image of the structure Opens in a new window - link to the reference on PubMed
26 ethanol ND L-type Ca2+ channel mRNA   Opens in a new window - link to the reference on PubMed
27 dimethyl sulfoxide (DMSO) ionic interaction    Image of the structure Opens in a new window - link to the reference on PubMed
28 6-furfuryladenine (kinetin) ND IKBKAP
mRNA
 Image of the structure Opens in a new window - link to the reference on PubMed
29 etoposide (VP16) Topo II inhibition? CASP-2 exon 9  Image of the structure Opens in a new window - link to the reference on PubMed
30 epigallocatechin gallate (EGCG) down-regulate the expression of hnRNP A2/B1 SMN2
exon 7 IKBKAP mRNA
 Image of the structure Opens in a new window - link to the reference on PubMedOpens in a new window - link to the reference on PubMed
31 cucurmin ND SMN2
exon 7
 Image of the structure Opens in a new window - link to the reference on PubMed
32 resveratrol ND SMN2
exon 7
 Image of the structure Opens in a new window - link to the reference on PubMed