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Alternative Splicing: Role in Cancer Development and Progression
Full text linkAlternative 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 aberrant alternative
splicing associated with neoplastic transformation. Moreover,
it illustrates the fact that signal transduction routes that are
frequently altered in cancer cells, such as the RAS/ERK and
the PI3K/AKT pathways, can modulate alternative splicing
events through the direct or indirect phosphorylation of
splicing regulatory proteins. Thus, protein kinases and phosphatases
involved in this step of gene expression regulation
may provide exciting opportunities for novel drug design.
A. Best et al. describe the emerging role of Tra2, an
SR-related protein, in human cancer. The gene encoding this
splicing factor is amplified in various types of cancer and
the increased expression of Tra2 is associated with cancer
cell survival. Interestingly, the Tra2 gene is a transcriptional
target of the proto-oncogene ETS-1, whereas known Tra2
splicing targets play key roles in cancer cells, where they affect
metastasis, proliferation, and cell survival. These observations
point to regulation of Tra2 expression in cancer cells
as an important step in tumorigenesis.
The review by Z. Siegfried et al. gives a series of specific
examples that cover misregulated alternative splicing events
affecting both the Ras-MAPK and PI3K-mTOR signalling
pathways during carcinogenesis.These pathways show extensive
crosstalk and are commonly altered in many cancers by
genetic and epigenetic aberrations. This article also addresses
how these signalling pathways play key roles in the transmission
of extracellular signals to the splicing machinery and to
specific RNA-binding proteins that ultimately regulate exon
definition events.
C. Jackson et al. give an overview on a topic of significant
clinical interest: the roles (often opposed) of the HER2 splice
isoforms in breast cancer progression and drug resistance.
M. P. Paronetto describes the function of the Ewing
Sarcoma protein (EWS) in cancer biology. EWS is best
known for its involvement in translocations associated with
sarcomas. Recent evidence has implicated EWS in the regulation
of DNA damage response (DDR) in cancer. EWS is a
multifunctional protein thought to help coordinate multiple
steps in the synthesis and processing of pre-mRNAs. This
review illustrates in detail the biochemical features and the
physiological roles of this RNA binding protein and provides
some hints on its possible contribution to human cancer.
Other two reviews give a series of specific examples of
cancer-associated splicing variants. C. Sette discusses the
growing evidence that dysregulated alternative splicing is a
major factor in the remarkable biological heterogeneity of
prostate cancer. Key genes, including the androgen receptor
itself, are alternatively spliced, thereby expressing isoforms
with opposing functions. The review also illustrates how
the regulation of alternative splicing is likely to present
novel opportunities in the diagnosis, prognosis, and treatment
of prostate cancer. S. Bonomi et al. deal with novel
information on how alternative splice variants of many
cancer-related genes can directly contribute to the oncogenic
phenotype, focusing on a number of processes involved in
cancer progression, such as response to hypoxia, migration,
invasion, and metastasis. Furthermore, they discuss
some significant examples of alternative splicing isoforms
selectively expressed by tumors and not by normal tissues,
which may not only represent diagnostic and prognostic
tumor biomarkers, but also provide potential targets for the
development of new therapeutic strategies.
In their article, L. Spraggon and L. Cartegni focus on the
role of U1 snRNP, an essential component of the splicing
machinery, in the regulation of alternative polyadenylation
and they strongly emphasize its implications in cancer pathogenesis.
Moreover, this review underlines the interesting
possibility of manipulating this U1 snRNP function for
anticancer therapeutic purposes.
Lastly, S. Barberan-Soler and J. M. Ragle give an overview
of the advantages of using the nematode Caenorhabditis
elegans to study splicing regulation in vivo. Importantly,
a large percentage of genes undergo alternative splicing
also in this simple and genetically useful organism. A big
proportion of these events are functional, conserved, and
under strict regulation across development, suggesting that
their investigation is likely to provide general mechanisms of
regulation that can be applied also to human genes. Notably,
the review illustrates several examples of alternatively spliced
genes that have human homologues implicated in cancer
biology.
We hope that this special issue will attract the attention of
researchers on new progresses in the fields of alternative splicing
and cancer. In particular, the articles presented herein
might highlight how this posttranscriptional mechanism of
gene expression plays important roles in the generation
of oncogenes and tumor suppressors, describe its interplay
with signaling pathways, and suggest how our knowledge
of these processes is leading to a better comprehension
of malignant transformation, thus helping develop novel
therapeutic strategies for the treatment of cancers
Altered expression of heterogenous nuclear ribonucleoproteins and SR factors in human colon adenocarcinomas
No full textAlternative splicing is part of the expression program of a wide number of genes implicated in cell growth and differentiation. Although the occurrence of inappropriate alternative splicing in tumors has started to emerge, the underlying molecular mechanisms have been, thus far, largely unexplored. We have investigated the alternative splicing pattern of the CD44 gene in specimens of nonfamilial colon adenocarcinomas at different stages of tumor progression. In the same patients, we have assessed by Northern blotting analysis the mRNA levels of different heterogeneous nuclear ribonucleoproteins and SR factors, all involved in pre-mRNA splicing and, more in general, in mRNA maturation. The results of this analysis highlight a general rule for the mode of splicing of the CD44 pre-mRNA. Moreover, we found that the mRNA levels of different SR proteins in tumor specimens are different from, and usually lower than, those detected in samples of nonpathological tissue adjacent to the tumor. Quantitative analysis demonstrates that, in tumors, the mRNA levels of ASF, SRp40, SRp55, and SRp75, when normalized to those of heterogeneous nuclear ribonucleoprotein A1, are lower than those of SRp20 and SRp30. Interestingly, this reduction is more drastic in patients showing a more altered CD44 splicing pattern and seems to be related to the propensity to develop metastases
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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