Alternative Splicing Regulation of Cancer-Related Pathways in<i>Caenorhabditis elegans</i>: An In Vivo Model System with a Powerful Reverse Genetics Toolbox

Barberán-Soler, Sergio; Ragle, James Matthew

doi:10.1155/2013/636050

Cited by 2 publications

(2 citation statements)

References 90 publications

(104 reference statements)

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“…Roughly 25% of protein-coding genes in C. elegans have multiple isoform annotations, with each gene producing 2.2 isoforms on average (Ramani et al 2011). In addition, many C. elegans trans-acting alternative splicing factors and their targeted cis-elements are conserved in mammals, making these worms an excellent model organism to study human diseases related to splicing factors (Kabat et al 2006;Zahler 2012;Barberan-Soler and Ragle 2013). The 5 ′ splice site consensus sequence in C. elegans is similar to other eukaryotes.…”

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Coordinated tissue-specific regulation of adjacent alternative 3′ splice sites inC. elegans

et al. 2015

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Adjacent alternative 3′ splice sites, those separated by ≤18 nucleotides, provide a unique problem in the study of alternative splicing regulation; there is overlap of the cis-elements that define the adjacent sites. Identification of the intron's 3 ′ end depends upon sequence elements that define the branchpoint, polypyrimidine tract, and terminal AG dinucleotide. Starting with RNA-seq data from germline-enriched and somatic cell-enriched Caenorhabditis elegans samples, we identify hundreds of introns with adjacent alternative 3 ′ splice sites. We identify 203 events that undergo tissue-specific alternative splicing. For these, the regulation is monodirectional, with somatic cells preferring to splice at the distal 3 ′ splice site (furthest from the 5 ′ end of the intron) and germline cells showing a distinct shift toward usage of the adjacent proximal 3 ′ splice site (closer to the 5 ′ end of the intron). Splicing patterns in somatic cells follow C. elegans consensus rules of 3 ′ splice site definition; a short stretch of pyrimidines preceding an AG dinucleotide. Splicing in germline cells occurs at proximal 3 ′ splice sites that lack a preceding polypyrimidine tract, and in three instances the germline-specific site lacks the AG dinucleotide. We provide evidence that use of germline-specific proximal 3 ′ splice sites is conserved across Caenorhabditis species. We propose that there are differences between germline and somatic cells in the way that the basal splicing machinery functions to determine the intron terminus. [Supplemental material is available for this article.]Alternative splicing is a highly regulated process by which a cell can produce multiple messenger RNAs, potentially encoding multiple proteins, from a common precursor transcript. The de novo assembly of a spliceosome on each intron of a pre-mRNA transcript requires cis-elements within the intron that are recognized as signals marking the beginning, end, and branchpoint (Ares and Weiser 1995). A cassette exon is a form of alternative splicing in which an exon is either included or skipped in the mature mRNA. Conserved enhancer or silencer elements within the exon or the surrounding introns interact with an array of constitutive and tissue-specific trans-factors that promote or inhibit assembly of a functional spliceosome (Wang and Burge 2008). The use of alternative 3 ′ or 5 ′ splice sites modifies gene expression by including or skipping coding sequences at the ends of exons. Many examples of adjacent alternative 3 ′ splice sites, defined as being separated by 18 nucleotides (nt) or less, have been observed. In many species, a form of alternative 3 ′ splice site usage has been identified in which the alternative splicing acceptors are only 3 nt apart. Except for the rare example of AC dinucleotides observed for substrates of the minor spliceosome, introns end with AG dinucleotides. Alternative 3 ′ splice sites separated by only 3 nt are referred to as NAGNAGs, as the end of the intron consists of two AG splice acceptors separated by 3 nt. A...

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Coordinated tissue-specific regulation of adjacent alternative 3′ splice sites inC. elegans

et al. 2015

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“…Its biological qualities can allow the improvement of the visibility and understanding of pathological diseases in humans and other multicellular beings. Some of the advantages of using C. elegans as a model for experimentation in vivo in this study are: Its perceptible phenotypes, the visibility of their internal organs, short life cycle (3 weeks), and the ability to adapt to different conditions in the laboratory [8] , [9] .…”

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The Annona muricata leaf ethanol extract affects mobility and reproduction in mutant strain NB327 Caenorhabditis elegans

Bustos

Jiménez

Mora

2017

Biochemistry and Biophysics Reports

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The C. elegans NB327 mutant strain is characterized for the knockdown of the dic-1 gene. The dic-1 gene is homologous to the dice-1 gene in humans, encoding the protein DICE-1 as a tumor suppressor. Absence or under-regulation of the dice-1 gene can be reflected in lung and prostate cancer [17], [18]. This study evaluated the effect of EEAML on the C. elegans NB327 mutant strain. Phenotypic aspects such as morphology, body length, locomotion, and reproductive behaviour were analyzed. It is important to emphasize that the strain presents a phenotype characteristic with respect to egg laying and hatching. Reported studies showed that Annona muricata extract and its active components evidence anti-cancer and anti-tumor effects, through experimentation in vivo and in vitro models. However, neurotoxicity has been reported as a side effect. The results showed that the mutant strain NB327 was exposed to EEAML (5 mg/ml) concentration, it showed a significant decrease in average locomotion, resulting in 13 undulations in 30 s. This contrasts with the control strain's 17.5 undulations in 30 s. Similarly, the number of progenies was reduced from 188 progenies (control strain) to 114 and 92 progenies at the dose of (1 mg/ml and 5 mg/m) EEAML. The results of this study suggest that EEAML has a possible neurotoxic effect in concentrations equal to or greater than 5 mg/ml. Also, it does not have positive effects on the mutant strain of Caenorhabditis elegans NB327 phenotype.

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Alternative Splicing Regulation of Cancer-Related Pathways inCaenorhabditis elegans: An In Vivo Model System with a Powerful Reverse Genetics Toolbox

Cited by 2 publications

References 90 publications

Coordinated tissue-specific regulation of adjacent alternative 3′ splice sites inC. elegans

Coordinated tissue-specific regulation of adjacent alternative 3′ splice sites inC. elegans

The Annona muricata leaf ethanol extract affects mobility and reproduction in mutant strain NB327 Caenorhabditis elegans

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