Alternatively Spliced Genes
may play a role in regulating alternative
splicing of other cell-death genes.
Another example of the complexity of
splicing regulatory elements is in the al-
ternative splicing of exon 10 in the human
gene. Alternative splicing of this exon
is associated with the pathogenesis of
dementias (Sect. 3.1). In this case, both
exonic and intronic regulatory elements
play important roles in controlling exon
10 inclusion. In addition, in the exonic re-
gion, both positive and negative elements
are involved and form a multidomain com-
posite regulatory element.
Trans-acting Splicing Regulators
The recognition and selection of splice
sites are determined during spliceosome
spliceosomal formation. Splicing activa-
tors facilitate interaction of U1snRNP with
splice site and of U2snRNP with 3
site, whereas splicing repressors suppress
the recognition of splice sites. A number
of proteins involved in spliceosome assem-
bly also play important roles in regulating
alternative splicing (see Table 1).
Several families of splicing activators
have been reported (Table 3). SR proteins
are among the best characterized splic-
ing activators. The interactions between
SR proteins and ESEs play a critical role
in exon recognition by the spliceosome.
ESEs are present in both constitutively
and alternatively spliced exons. By medi-
ating protein–protein and RNA–protein
interactions during early steps of spliceo-
some assembly, SR proteins coordinate
the communication between 5
and 3
splice sites and promote interactions be-
tween exonic enhancers and splice sites.
ticomponent complexes, containing not
only SR proteins but also other RS do-
main–containing proteins such as U2AF.
Some RS domain–containing proteins,
such as SRm300 and SRm160, act as
coactivators for ESE function. The RS do-
main in SR proteins can be differentially
phosphorylated, providing another level of
regulation. The phosphorylation status of
SR proteins regulates protein–protein in-
teractions, intracellular distribution, and
activities of SR proteins. Differential phos-
phorylation of SR proteins has been shown
to play a role in regulating gene expression
during development.
SF1, KSRP, NOVA-1, and rSLM-2 are
RNA-binding proteins containing hetero-
geneous nuclear ribonucleoprotein K-type
homology (KH) domain. They can en-
hance splicing by interacting with ISEs.
SF1, a protein important for branch site
recognition during spliceosome assembly,
binds to GGGGCUG repeats in an ISE
to activate the recognition of a 6-bp mi-
cro exon in cTNT gene. KSRP interacts
with UGCAUG sequence and stimulates
the neuronal-speci±c exon inclusion in c-
src. NOVA-1 enhances the splicing of exon
E3A in the
2 subunit of the glycine re-
ceptor gene (GlyR
2). The rat Sam68-like
mammalian protein (rSLM-2) is a mem-
ber of the STAR (signal transduction and
activation of RNA) protein family. It can in-
fluence the splicing pattern of the CD44v5,
human transformer-2beta, and tau mini-
genes in transfected cells.
Several members of CUG-BP and ETR-
like factors (CELF) family activate the
splicing of genes including cTNT, muscle-
speci±c chloride channel, insulin receptor,
and NMDA R1. Some of these CELF
proteins activate splicing by interacting
with ISEs.
TIA-1, a mammalian homolog of yeast
NAM8 protein, interacts with the U-rich
intronic sequence adjacent to the 5
site of the K-SAM alternative exon in the
FGFR2 gene. The activation of this splice
previous page 148 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 150 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off