TY - JOUR
T1 - Alternative splicing: Role in cancer development and progression
AU - Sette, Claudio
AU - Ladomery, Michael
AU - Ghigna, Claudia
PY - 2013
Y1 - 2013
N2 - Alternative splicing of precursor messenger RNAs (premRNAs)
is a fundamental step in the regulation of gene
expression. This processing step of the nascent messenger
amplifies the coding potential of eukaryotic genomes by
allowing the production of multiple protein isoforms with
distinct structural and functional properties. The advent
of high-throughput sequencing techniques has recently
revealed that alternative splicing of exons and introns represents
a major source of proteomic diversity in complex organisms
characterized by a limited number of protein-coding
genes. Nevertheless, the evolutionary advantage provided by
alternative splicing can also turn into a source of deleterious
problems for the organism. Indeed, the extreme flexibility
of its regulation, which relies on the combinatorial action
of multiple non stringent factors, is subject to errors and
the aberrant splicing of key genes can result in the onset of
many human genetic and sporadic diseases. In this regard,
mounting evidence illustrates how changes in alternative
splicing patterns of specific genes is an important tool used
by cancer cells to produce protein isoforms involved in all
areas of cancer cell biology, including numerous aspects of
tumor establishment, progression, and resistance to therapeutic
treatments. Importantly, cancer-specific splice variants
have the potential to become suitable therapeutic targets for
human cancer, as novel tools to correct splicing defects are
being developed and, in some cases, have entered clinical
trials for other human diseases, such as spinal muscular
atrophy. Nevertheless, these findings are likely to represent
just the tip of the iceberg and important questions regarding
the role of alternative splicing in cancer still remain to be
addressed.
The main focus of this special issue is to emphasize key
mechanisms involved in oncogenic splicing changes, their
connection with other steps of gene expression, and the
therapeutic potential of cancer-associated alternative splicing
isoforms.
More specifically, M. Ladomery discusses alternative
splicing in the context of the so-called hallmarks of cancer,
originally proposed by Hanahan and Weinberg in 2000.
The list of hallmarks was originally six; recently it was
augmented to ten. M. Ladomery proposes that a comprehensive
dysregulation of alternative splicing could, in itself,
be considered yet another hallmark of cancer. The idea is
that the aberrant expression and activity of key oncogenic
splicing factors and/or their regulatory kinases could lead
to a systematic change in gene expression by favouring the
concurrent production of several oncogenic splice variants of
genes involved in critical biological aspects of tumour cells.
S. C. Lenzken et al. review our current knowledge of the
role of alternative splicing in the multiple and various aspects
of the DNA damage response (DDR) and the control of
genome stability. This review illustrates several mechanisms
through which pre-mRNA splicing and genomic stability can
influence each other and contribute to tumorigenesis.
M. Romano and colleagues draw attention to the function
that pseudoexons and pseudointrons can play directly in
cancer pathology. These sequences can be found in genes
that have well-established roles in cancer, including BRCA1,
2 International Journal of Cell Biology
BRCA2, NF-1, and ATM. They describe the mechanisms
through which pseudoexons and pseudointrons can be activated
or repressed. In addition, they discuss their potential
use as tumour biomarkers to provide a more detailed staging
and grading of cancer.
C. Naro and C. Sette discuss the key role that reversible
phosphorylation plays in the regulation of alternative splicing.
Both splice factors and core components of the spliceosome
are affected by phosphorylation. The review focuses
on the role of protein kinases and phosphatases whose
activity has specifically been linked to
AB - Alternative splicing of precursor messenger RNAs (premRNAs)
is a fundamental step in the regulation of gene
expression. This processing step of the nascent messenger
amplifies the coding potential of eukaryotic genomes by
allowing the production of multiple protein isoforms with
distinct structural and functional properties. The advent
of high-throughput sequencing techniques has recently
revealed that alternative splicing of exons and introns represents
a major source of proteomic diversity in complex organisms
characterized by a limited number of protein-coding
genes. Nevertheless, the evolutionary advantage provided by
alternative splicing can also turn into a source of deleterious
problems for the organism. Indeed, the extreme flexibility
of its regulation, which relies on the combinatorial action
of multiple non stringent factors, is subject to errors and
the aberrant splicing of key genes can result in the onset of
many human genetic and sporadic diseases. In this regard,
mounting evidence illustrates how changes in alternative
splicing patterns of specific genes is an important tool used
by cancer cells to produce protein isoforms involved in all
areas of cancer cell biology, including numerous aspects of
tumor establishment, progression, and resistance to therapeutic
treatments. Importantly, cancer-specific splice variants
have the potential to become suitable therapeutic targets for
human cancer, as novel tools to correct splicing defects are
being developed and, in some cases, have entered clinical
trials for other human diseases, such as spinal muscular
atrophy. Nevertheless, these findings are likely to represent
just the tip of the iceberg and important questions regarding
the role of alternative splicing in cancer still remain to be
addressed.
The main focus of this special issue is to emphasize key
mechanisms involved in oncogenic splicing changes, their
connection with other steps of gene expression, and the
therapeutic potential of cancer-associated alternative splicing
isoforms.
More specifically, M. Ladomery discusses alternative
splicing in the context of the so-called hallmarks of cancer,
originally proposed by Hanahan and Weinberg in 2000.
The list of hallmarks was originally six; recently it was
augmented to ten. M. Ladomery proposes that a comprehensive
dysregulation of alternative splicing could, in itself,
be considered yet another hallmark of cancer. The idea is
that the aberrant expression and activity of key oncogenic
splicing factors and/or their regulatory kinases could lead
to a systematic change in gene expression by favouring the
concurrent production of several oncogenic splice variants of
genes involved in critical biological aspects of tumour cells.
S. C. Lenzken et al. review our current knowledge of the
role of alternative splicing in the multiple and various aspects
of the DNA damage response (DDR) and the control of
genome stability. This review illustrates several mechanisms
through which pre-mRNA splicing and genomic stability can
influence each other and contribute to tumorigenesis.
M. Romano and colleagues draw attention to the function
that pseudoexons and pseudointrons can play directly in
cancer pathology. These sequences can be found in genes
that have well-established roles in cancer, including BRCA1,
2 International Journal of Cell Biology
BRCA2, NF-1, and ATM. They describe the mechanisms
through which pseudoexons and pseudointrons can be activated
or repressed. In addition, they discuss their potential
use as tumour biomarkers to provide a more detailed staging
and grading of cancer.
C. Naro and C. Sette discuss the key role that reversible
phosphorylation plays in the regulation of alternative splicing.
Both splice factors and core components of the spliceosome
are affected by phosphorylation. The review focuses
on the role of protein kinases and phosphatases whose
activity has specifically been linked to
KW - Cell Biology
KW - Cell Biology
UR - http://hdl.handle.net/10807/124892
UR - http://www.hindawi.com/journals/ijcb/
U2 - 10.1155/2013/421606
DO - 10.1155/2013/421606
M3 - Article
SN - 1687-8876
VL - 2013
SP - N/A-N/A
JO - International Journal of Cell Biology
JF - International Journal of Cell Biology
ER -