150
Alternatively Spliced Genes
been found, neuron-enriched (nPTB,) and
smooth muscle–enriched (SmPTB). For
example, nPTB can compete with PTB to
promote inclusion of neuronal-speci±c N1
exon inclusion in c-src. The expression of
SmPTBcorre
la
tesw
i
ththesmoo
thmus
-
cle–speci±c suppression of
α
-tropomyosin
exon 3, which is included in nonsmooth
muscle cells. The release of PTB sup-
pression can be also achieved by cell-type
speci±c CELF proteins such as ETR3 and
Napor-1.
One exception to the general inhibitory
activity of PTB has been reported where
PTB stimulates the inclusion of an alter-
native 3
0
-terminal exon. In this case, the
splicing regulation is coupled with alter-
native polyadenylation. In addition, PTB
has also been implicated in translational
control of viral transcripts. More compre-
hensive understanding of the biological
roles of PTB in gene regulation requires
further investigation.
Several proteins containing an RS do-
main and
RRM-cs domains have
also
been reported to act as splicing repres-
sors, including SRrp30c, SRrp35, SRp38,
and SRrp40 (see Table 3). SR proteins are
generally hyperphosphorylated by the ki-
nase SRPK1. Dephosphorylated SRp38 is
required for the splicing repression in mi-
totic cells. Another RS domain-containing
protein,
the
Drosophila
suppressor-of-
white-apricot protein (SWAP) suppresses
its own pre-mRNA splicing.
An RRM-containing spliceosomal pro-
tein, SPF45, represents a late-acting splic-
ing regulator. In
Drosophila
,SPF45b
locks
splicing at the second step by interact-
ing with Sex-lethal (Sxl) protein, indicating
that 3
0
splice site recognition and splicing
regulation can occur at the second cat-
alytic step.
Proteins containing KH domains can
also
act
as
splicing
repressors.
For
example, a nuclear isoform of quaking (qk)
protein, QKI-5, regulates alternative splic-
ing of myelin-associated glycoprotein gene
by interacting with an intronic splicing
repressor
element.
A
Drosophila
splic-
ing repressor, P-element somatic inhibitor
(PSI), is required for the soma-speci±c
inhibition of splicing of P-element pre-
mRNA both
in vitro
and
in vivo
.
Several splicing regulators can act as
either positive or negative splicing regula-
tors, depending on the sequence context
of the pre-mRNA substrates. We classify
these splicing regulators as bifunctional
splicing
regulators.
Some
SR
proteins
or SR-domain containing proteins can
repress splicing of certain pre-mRNAs
but activate splicing of other substrates.
SRrp86 is an 86-kDa related to SR pro-
teins. It can function as either an activator
or a repressor by regulating the activ-
ity of other SR proteins. Other proteins
can repress splicing by interacting with
SR proteins. For example, an ASF/SF2-
interacting protein, p32, was shown to act
as a splicing regulator by inactivating the
function of ASF/SF2.
H
n
R
N
PHa
n
dt
h
er
e
l
a
t
e
dp
r
o
t
e
i
n
hnRNP F contain three RRMs of RNP-
cs type. HnRNP H interacts with G-rich
elements in either splicing enhancers or
silencers. When binding to
a
splicing
enhancer in the HIV env gene, hnRNP
H acts as an activator by promoting the
assembly of a complex containing SC35
and U1snRNP.
When interacting with
ESSs in the
β
-tropomyosin pre-mRNA
or HIV Tat exon 2, or with a negative
regulator of splicing (NRS) in the Rous
Sarcoma Virus (RSV) genome, hnRNP H
serves as a splicing repressor.
Napor1, a splice variant of ETR3, is
expressed at a high level in the forebrain
but at a low level in the cerebellum.
Overexpression of Napor1 exerts opposite
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