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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.
|
|
Small Molecule
Name |
Mechanism |
Regulated Exon |
Structure |
Reference |
|
Histone Deacetylase (HDAC) Inhibitors |
|
1 |
sodium butyrate |
HDAC
inhibitor
|
SMN2
exon 7
|
|
 |
|
2 |
valproic acid |
HDAC
inhibitor
|
SMN2
exon 7
|
 |
|
|
3 |
sodium 4-phenylbutyrate |
HDAC
inhibitor
|
SMN2
exon 7
|
 |
|
|
4 |
N-hydroxyl-7-(4-(dimethylamino)benzoyl)
aminoheptanamide (M344) |
HDAC
inhibitor
|
SMN2
exon 7
|
 |
|
|
5 |
suberoylanilide hydroxamic acid (SAHA) |
HDAC
inhibitor
|
SMN2
exon 7 |
 |
|
|
Kinase Inhibitors |
|
6 |
aclarubicin |
Topo I |
SMN2
exon 7
|
 |
|
|
7 |
camptothecin |
Topo I |
CASP-2
exon 9 |
 |
|
|
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
|
 |
|
|
9 |
isodiospyrin |
Topo I |
Not defined
( ND)
|
 |
|
|
10 |
(Z)-1-(3-ethyl-5-methoxy-2, 3-dihydrobenzothiazol-2-ylidene)
propan-2-one (TG003) |
CLK kinases |
Clk1/sty exon 2 and E1A |
 |
|
|
11 |
lithium chloride |
GSK3 |
Tau
exon 10
|
LiCl |
|
|
12 |
N-(4-methoxybenzyl)-N’-(5-nitro-1,3-thiazol-2-yl)urea
(AR-A014418) |
GSK3 |
Tau
exon 10 |
 |
|
|
Phosphatase Inhibitors |
|
13 |
sodium orthovanadate |
non-specific inhibitor |
SMN2
exon 7
|
Na3VO4 |
|
|
14 |
N-(hexanoyl)sphingosine (C6-ceramide) |
PP1 regulation |
Bcl-X
and
CASP-9
|
 |
|
|
15 |
tautomycin |
PP1 inhibition
|
SMN2
exon 7 and multiple other exons
|
 |
|
|
16 |
cantharidin |
PP1 inhibition
|
SMN2
exon 7
|
 |
|
|
cAMP Pathway |
|
17 |
rac-2-[4-(1-oxo-2-isoindolinyl)phenyl]propionic acid (indoprofen) |
phospho-diesterase inhibitor? |
SMN2
|
 |
|
|
18 |
2-(tert-butylamino)-1-(4-hydroxy-3-hydroxymethylphenyl)ethanol
sulfate (salbutamol) |
adrenergic antagonist |
SMN2
exon 7
|
 |
|
|
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
|
 |
|
|
Coupling of Transcription and Splicing |
|
20 |
dexamethazone |
coupling of transcription and splicing |
Insulin receptor mRNA |
 |
|
|
21 |
dihydroepiandrosterone (DHEA) |
coupling of transcription and splicing |
Stress axis-regulated (STREX)
exon |
 |
|
|
22 |
steroid hormones |
ND |
Reporter CD44 mini-gene |
|
|
|
Ion Channels and Electrochemical Gradients |
|
23 |
5-(N-ethyl-N-isopropyl)amiloride (EIPA) |
change in ion gradient |
SMN2
|
 |
|
|
24 |
glutamate |
change in ion gradient |
Ania-6
mRNA
|
|
|
|
Unknown Role |
|
25 |
hydroxyurea |
ND |
SMN2
exon 7
|
 |
|
|
26 |
ethanol |
ND |
L-type Ca2+
channel mRNA |
|
|
|
27 |
dimethyl sulfoxide (DMSO)
|
ionic
interaction
|
|
 |
|
|
28 |
6-furfuryladenine (kinetin) |
ND |
IKBKAP
mRNA
|
 |
|
|
29 |
etoposide (VP16) |
Topo II inhibition? |
CASP-2
exon 9 |
 |
|
|
30 |
epigallocatechin gallate (EGCG) |
down-regulate the expression
of hnRNP A2/B1 |
SMN2
exon 7
IKBKAP
mRNA
|
 |
|
|
31 |
cucurmin |
ND |
SMN2
exon 7
|
 |
|
|
32 |
resveratrol |
ND |
SMN2
exon 7
|
 |
|
|
|