Alternatively Spliced Genes
143
occur in the protein-coding regions or in
the regulatory regions of genes, including
both 5
0
and 3
0
untranslated regions. Alter-
native splicing can affect peptide coding
capacity or influence mRNA stability or
translational control of the transcription
products. Alternative splicing regulation
can also be coupled with transcription,
polyadenylation, RNA editing, or mRNA
exporting processes. A recent example for
the coupling of splicing with other pro-
cesses of gene regulation is that steroid
hormone
receptors
can
simultaneously
regulate transcription and alternative splic-
ing by recruiting coregulators involved in
both processes. In addition, alternative
splicing can affect posttranslational modi-
Fcations of protein products.
2.1.1
Different Patterns of Alternative
Splicing
A number of distinct alternative splic-
ing patterns have been reported (±ig. 5).
Most common alternative splicing events
include exon inclusion/skipping, intron
removal/retention, and alternative selec-
tion of competing 5
0
or 3
0
splice sites.
More complex patterns of alternative splic-
ing include mutually exclusive or cassette
types of exon inclusion. Alternative selec-
tion of terminal exons can be coupled with
differential promoter usage or polyadeny-
lation. ±urthermore, recent studies have
documented
possible
alternative
trans-
splicing of mammalian genes, although
it may occur only at a low frequency
in mammals.
2.1.2
Alternative Splicing and Genetic
Diversity
Alternative
splicing
regulates
gene
ac-
tivities involved in every aspect of cell
survival
and
function.
It
is
a
major
mechanism for generating the complexity
of
mammalian
proteomes.
Alternative
splicing
contributes
to
proteome
ex-
pansion by a number of mechanisms,
such
as
the
usage
of
distinct
trans-
lation
start
sites,
in-frame
nucleotide
deletion or insertion, changes in pep-
tide sequence, and alternative usage of
different translation stop codons. Such
changes in peptide sequence or length
may
lead
to
the
formation
of
pro-
teins
with
distinct
properties,
includ-
ing biochemical/biophysical characteris-
tics, subcellular localization (secreted ver-
sus
membrane
associated,
membrane-
tethered versus cytoplasmic, cytoplasmic
versus nuclear), posttranslational modiF-
cations (glycosylation, phosphorylation, or
lipid modiFcation), or interactions with
other cellular components.
Alternative splicing can be an excellent
mechanism for generating functionally an-
tagonistic products from the same genetic
locus and for the Fne-tuning of gene ac-
tivities at the posttranscriptional level. ±or
example, alternative splicing of a number
of genes critical for cell death leads to the
formation of both cell death–promoting
and cell death–preventing splicing iso-
forms. These include genes encoding for
death ligands, death receptors, Bcl-2 super-
family of death regulators, caspases, and
other cell-death regulatory genes. Several
human caspase genes utilize alternative
splicing to produce protein products that
either contain or lack their enzyme active
sites, resulting in antagonistic activities in
cell death.
The nervous system is a good exam-
ple where alternative splicing is utilized
to generate extreme functional diversity. A
vast number of genes involved in neu-
ral development and function undergo
complex alternative splicing. Some genes
encoding neural receptors and axon guid-
ance molecules can generate hundreds to
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