152
Alternatively Spliced Genes
splicing events of different genes appear
to be coregulated by the same protein. For
example, the splicing regulator PTB can
differentially recognize neural and non-
neural substrates. The expression pattern
of PTB in different regions of the brain
at different developmental stages supports
a role for PTB to act as an alternative
splicing coordinator for different splicing
target genes.
2.4
Regulation of Alternative Splicing in
Response to Extracellular Stimuli
Extracellular signals can induce changes
in alternative splicing of different genes.
For
example,
growth
factors
or
hor-
mones stimulate alternative splicing of
intracellular responsive genes. Treatment
with growth factors induces changes in
alternative
splicing
of
phosphotyrosine
phosphatase
PTP-1B
gene.
The
alter-
native
splicing
pattern
of
protein
ki-
nase
C
beta
is
changed
by
insulin.
Activation
of
calmodulin-dependent
ki-
nases (CaM kinases) stimulates changes
in
alternative
splicing
of
BK
potas-
sium channels. In most cases, however,
signal
transduction
pathways
involved
in
splicing
regulation
have
not
been
characterized.
A number of genes important for the
functioning of the nervous system show
activity-dependent changes in their splic-
ing.
Alternative
splicing of
syntaxin
3
changes in response to induction of long-
term potentiation. NMDAR1 alternative
splicing is modulated by both pH and
Ca
2
+
.
Stress
hormones
regulate
alter-
native splicing of potassium channels.
A
cis-acting
sequence
named
calcium-
responsive RNA element
(CaRRE) in the
stress-inducible exon of BK potassium
ch
ann
e
l
san
dinNMDAR
1e
x
on5h
a
s
been identiĀ±ed. This element mediates
CaM kinase-dependent repression of the
inclusion of the
CaRRE-containing ex-
ons.
The
mechanisms
by
which
the
CaRRE causes exon skipping remain to
be elucidated.
Drastic changes in the cell growth en-
vironment are expected to affect RNA
metabolism, including alternative splic-
ing. For example, ischemia in mice in-
duces changes in alternative splicing of
several genes examined. Accompanying
such changes in alternative splicing are
changes in the intracellular distribution
of several splicing regulators. It is possi-
ble that these splicing regulators undergo
changes in posttranslational modiĀ±cations
or at other levels induced by ischemia.
Chemical compounds, when adminis-
trated to animals or applied to cells in
culture, can also cause changes in alterna-
tive splicings. Sodium butyrate has been
tested in transgenic mice and shown to in-
crease exon 7 inclusion of the SMN gene.
Aclarubicin treatment induces changes in
SMN gene alternative splicing in cultured
cells. Treatment of A549 lung adenocarci-
noma cells with cell-permeable ceramide,
D-e-C(6) ceramide, downregulates the lev-
els
of
Bcl-xL
and
caspase
9b
splicing
isoforms. The functional responses of nu-
clear splicing machinery to drug treatment
opens the possibility of correcting aber-
rant or defective splicing using therapeutic
agents (Sect. 4.2).
3
Pre-mRNA Splicing and Human Diseases
Aberrant pre-mRNA splicing has been
implicated in the pathogenesis of a num-
ber of human diseases. Alterations, or
dysregulation of either constitutive pre-
mRNA splicing or alternative splicing can
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