scholarly journals Splicing Regulators and Their Roles in Cancer Biology and Therapy

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Maria Roméria da Silva ◽  
Gabriela Alves Moreira ◽  
Ronni Anderson Gonçalves da Silva ◽  
Éverton de Almeida Alves Barbosa ◽  
Raoni Pais Siqueira ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Cancer Biology ◽  
Single Gene ◽  
Tumor Biology ◽  
Sr Proteins ◽  
Protein Isoforms ◽  
Protein Expression Pattern ◽  
Regulatory Factors ◽  
Impact Pathways ◽  
Splicing Regulators

Alternative splicing allows cells to expand the encoding potential of their genomes. In this elegant mechanism, a single gene can yield protein isoforms with even antagonistic functions depending on the cellular physiological context. Alterations in splicing regulatory factors activity in cancer cells, however, can generate an abnormal protein expression pattern that promotes growth, survival, and other processes, which are relevant to tumor biology. In this review, we discuss dysregulated alternative splicing events and regulatory factors that impact pathways related to cancer. The SR proteins and their regulatory kinases SRPKs and CLKs have been frequently found altered in tumors and are examined in more detail. Finally, perspectives that support splicing machinery as target for the development of novel anticancer therapies are discussed.

scholarly journals Alternative splicing in endothelial cells: novel therapeutic opportunities in cancer angiogenesis

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Anna Di Matteo ◽  
Elisa Belloni ◽  
Davide Pradella ◽  
Ambra Cappelletto ◽  
Nina Volf ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Human Cancer ◽  
Single Gene ◽  
Predictive Biomarkers ◽  
Protein Isoforms ◽  
Therapeutic Interventions ◽  
Cancer Therapies ◽  
Functional Changes ◽  
Splicing Regulators ◽  
Multiple Protein

AbstractAlternative splicing (AS) is a pervasive molecular process generating multiple protein isoforms, from a single gene. It plays fundamental roles during development, differentiation and maintenance of tissue homeostasis, while aberrant AS is considered a hallmark of multiple diseases, including cancer. Cancer-restricted AS isoforms represent either predictive biomarkers for diagnosis/prognosis or targets for anti-cancer therapies. Here, we discuss the contribution of AS regulation in cancer angiogenesis, a complex process supporting disease development and progression. We consider AS programs acting in a specific and non-redundant manner to influence morphological and functional changes involved in cancer angiogenesis. In particular, we describe relevant AS variants or splicing regulators controlling either secreted or membrane-bound angiogenic factors, which may represent attractive targets for therapeutic interventions in human cancer.

scholarly journals Netrin Family: Role for Protein Isoforms in Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Caroline Suzanne Bruikman ◽  
Huayu Zhang ◽  
Anneli Maite Kemper ◽  
Janine Maria van Gils
Keyword(s):  
Cell Migration ◽  
Alternative Splicing ◽  
Special Interest ◽  
Tumor Biology ◽  
Family Members ◽  
Axonal Guidance ◽  
Protein Isoforms ◽  
Family Role ◽  
Associated Proteins

Netrins form a family of secreted and membrane-associated proteins. Netrins are involved in processes for axonal guidance, morphogenesis, and angiogenesis by regulating cell migration and survival. These processes are of special interest in tumor biology. From the netrin genes various isoforms are translated and regulated by alternative splicing. We review here the diversity of isoforms of the netrin family members and their known and potential roles in cancer.

scholarly journals Influence of Intron Length on Alternative Splicing of CD44

1998 ◽  
Vol 18 (10) ◽  
pp. 5930-5941 ◽  
Author(s):  
Martyn V. Bell ◽  
Alison E. Cowper ◽  
Marie-Paule Lefranc ◽  
John I. Bell ◽  
Gavin R. Screaton
Keyword(s):  
Alternative Splicing ◽  
Genomic Structure ◽  
Single Gene ◽  
Intron Length ◽  
Protein Isoforms ◽  
Major Influence ◽  
Eukaryotic Genes ◽  
Alternatively Spliced ◽  
Alternatively Spliced Exons

ABSTRACT Although the splicing of transcripts from most eukaryotic genes occurs in a constitutive fashion, some genes can undergo a process of alternative splicing. This is a genetically economical process which allows a single gene to give rise to several protein isoforms by the inclusion or exclusion of sequences into or from the mature mRNA. CD44 provides a unique example; more than 1,000 possible isoforms can be produced by the inclusion or exclusion of a central tandem array of 10 alternatively spliced exons. Certain alternatively spliced exons have been ascribed specific functions; however, independent regulation of the inclusion or skipping of each of these exons would clearly demand an extremely complex regulatory network. Such a network would involve the interaction of many exon-specific trans-acting factors with the pre-mRNA. Therefore, to assess whether the exons are indeed independently regulated, we have examined the alternative exon content of a large number of individual CD44 cDNA isoforms. This analysis shows that the downstream alternatively spliced exons are favored over those lying upstream and that alternative exons are often included in blocks rather than singly. Using a novel in vivo alternative splicing assay, we show that intron length has a major influence upon the alternative splicing of CD44. We propose a kinetic model in which short introns may overcome the poor recognition of alternatively spliced exons. These observations suggest that for CD44, intron length has been exploited in the evolution of the genomic structure to enable tissue-specific patterns of splicing to be maintained.

scholarly journals Abnormalities in alternative splicing in diabetes: therapeutic targets

2017 ◽  
Vol 59 (2) ◽  
pp. R93-R107 ◽  
Author(s):  
Zodwa Dlamini ◽  
Fortunate Mokoena ◽  
Rodney Hull
Keyword(s):  
Alternative Splicing ◽  
Single Gene ◽  
Treatment Options ◽  
Cell Mass ◽  
Biological Significance ◽  
Cost Effective ◽  
Significant Loss ◽  
Protein Isoforms ◽  
Β Cell ◽  
Therapeutic Tools

Diabetes mellitus (DM) is a non-communicable, metabolic disorder that affects 416 million individuals worldwide. Type 2 diabetes contributes to a vast 85–90% of the diabetes incidences while 10–15% of patients suffer from type 1 diabetes. These two predominant forms of DM cause a significant loss of functional pancreatic β-cell mass causing different degrees of insulin deficiency, most likely, due to increased β-cell apoptosis. Treatment options involve the use of insulin sensitisers, α-glucosidase inhibitors, and β-cell secretagogues which are often expensive, limited in efficacy and carry detrimental adverse effects. Cost-effective options for treatment exists in the form of herbal drugs, however, scientific validations of these widely used medicinal plants are still underway. Alternative splicing (AS) is a co-ordinated post-transcriptional process in which a single gene generates multiple mRNA transcripts which results in increased amounts of functionally different protein isoforms and in some cases aberrant splicing leads to metabolic disease. In this review, we explore the association of AS with metabolic alterations in DM and the biological significance of the abnormal splicing of some pathogenic diabetes-related genes. An understanding of the molecular mechanism behind abnormally spliced transcripts will aid in the development of new diagnostic, prognostic and therapeutic tools.

Human papillomavirus regulation of SR proteins

2010 ◽  
Vol 38 (4) ◽  
pp. 1116-1121 ◽  
Author(s):  
Melanie McFarlane ◽  
Sheila V. Graham
Keyword(s):  
Human Papillomavirus ◽  
Alternative Splicing ◽  
Sr Proteins ◽  
Hpv Infection ◽  
Splicing Factor ◽  
Sr Protein ◽  
Splicing Regulators ◽  
Constitutive Splicing ◽  
Rna Biogenesis ◽  
Specific Alternative

Splicing is a cellular process essential for mRNA biogenesis. There are two types of splicing: constitutive and alternative splicing. During constitutive splicing, non-coding intron sequences are removed and exonic coding sequences are spliced together to form mature mRNAs. Alternative splicing can maximize the coding capacity of the genome by specific alternative selection of exons from multi-exon metazoan pre-mRNAs. Splicing is a tightly regulated process, so when control is lost disease may occur. SR proteins (serine/arginine-rich proteins) are a family of highly conserved splicing regulators that are also involved in other steps in RNA biogenesis and expression. Many viruses have evolved to utilize the cellular splicing machinery to enhance their proteome from a limited number of genes. HPV (human papillomavirus) is an example of one such virus. The HPV transcription/replication factor E2 (early 2) specifically up-regulates expression of the SR proteins SF2/ASF (splicing factor 2/alternative splicing factor), SRp20 and SC35 in infected epithelial cells. These SR proteins are essential for viral RNA processing. SF2/ASF is a proto-oncogene that is also up-regulated in a number of cancers. For example, SF2/ASF, together with SRp20 and SC35 is selectively up-regulated in cervical tumours caused by persistent oncogenic HPV infection. However, the mode of SR protein up-regulation in tumours is different to the E2-directed transcriptional regulation in normal transient HPV infection. SR proteins could provide excellent targets for HPV antiviral therapy as well as anticancer therapy.

scholarly journals Identification of Genomewide Alternative Splicing Events in Sequential, Isogenic Clinical Isolates of Candida albicans Reveals a Novel Mechanism of Drug Resistance and Tolerance to Cellular Stresses

mSphere ◽  
2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Suraya Muzafar ◽  
Ravi Datta Sharma ◽  
Abdul Haseeb Shah ◽  
Naseem A. Gaur ◽  
Ujjaini Dasgupta ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Candida Albicans ◽  
Alternative Splicing ◽  
Rna Sequencing ◽  
Single Gene ◽  
Drug Susceptibility ◽  
Protein Isoforms ◽  
Sequencing Data ◽  
Splice Isoforms ◽  
Content Type

ABSTRACT Alternative splicing (AS)—a process by which a single gene gives rise to different protein isoforms in eukaryotes—has been implicated in many basic cellular processes, but little is known about its role in drug resistance and fungal pathogenesis. The most common human fungal pathogen, Candida albicans, has introns in 4 to 6% of its genes, the functions of which remain largely unknown. Here, we report AS regulating drug resistance in C. albicans. Comparative RNA-sequencing of two different sets of sequential, isogenic azole-sensitive and -resistant isolates of C. albicans revealed differential expression of splice isoforms of 14 genes. One of these was the superoxide dismutase gene SOD3, which contains a single intron. The sod3Δ/Δ mutant was susceptible to the antifungals amphotericin B (AMB) and menadione (MND). While AMB susceptibility was rescued by overexpression of both the spliced and unspliced SOD3 isoforms, only the spliced isoform could overcome MND susceptibility, demonstrating the functional relevance of this splicing in developing drug resistance. Furthermore, unlike AMB, MND inhibits SOD3 splicing and acts as a splicing inhibitor. Consistent with these observations, MND exposure resulted in increased levels of unspliced SOD3 isoform that are unable to scavenge reactive oxygen species (ROS), resulting in increased drug susceptibility. Collectively, these observations suggest that AS is a novel mechanism for stress adaptation and overcoming drug susceptibility in C. albicans. IMPORTANCE The emergence of resistance in Candida albicans, an opportunistic pathogen, against the commonly used antifungals is becoming a major obstacle in its treatment. The necessity to identify new drug targets demands fundamental insights into the mechanisms used by this organism to develop drug resistance. C. albicans has introns in 4 to 6% of its genes, the functions of which remain largely unknown. Using the RNA-sequencing data from isogenic pairs of azole-sensitive and -resistant isolates of C. albicans, here, we show how C. albicans uses modulations in mRNA splicing to overcome antifungal drug stress.

scholarly journals Identification of genome-wide alternative splicing events in sequential, isogenic clinical isolates of Candida albicans reveals a mechanism important for drug resistance and tolerance to cellular stress

2021 ◽  
Vol 3 (12) ◽  
Author(s):  
Suraya Muzafar ◽  
Neeraj Chauhan ◽  
Ravi Datta Sharma ◽  
Rajendra Prasad
Keyword(s):  
Drug Resistance ◽  
Candida Albicans ◽  
Alternative Splicing ◽  
Differential Expression ◽  
Single Gene ◽  
Antifungal Drugs ◽  
Protein Isoforms ◽  
Gene Splicing ◽  
Cellular Processes ◽  
Genome Wide

Alternative gene splicing (AS) is a process by which a single gene can give rise to different protein isoforms, generating proteome diversity. Despite recent advances in our understanding of AS in basic cellular processes, the role of AS in drug resistance and fungal pathogenesis is poorly understood. In Candida albicans, approximately 6% of the genes contain introns. Considering this low and random distribution of introns, we focused our study on alternative splicing (AS) and its impact on the development of drug resistance, an area largely unexplored in this yeast. We performed comparative RNA sequencing of sequential isogenic azole sensitive and resistant isolates of C. albicans. The analysis revealed differential expression of splice junctions/isoforms in 14 genes, between the drug sensitive and resistant isolates. Furthermore, C. albicans WT cells exposed to antifungal drugs, heat stress or metal deficiency also showed differential expression of isoforms for the genes undergoing AS. In this study we present data on the effect of AS on the function of SOD3. The C. albicans SOD3 has a single intron and is important for the removal of superoxide radicals. The overexpression of the two isoforms of SOD3 in its null background highlighted importance of spliced isoform in complementing the susceptibility to menadione. However, the two isoforms did not differ in rescuing the susceptibility of sod3Δ/Δto Amphotericin B. Collectively, these data suggest that AS may be a novel mechanism in C. albicans for stress adaptation and overcoming drug resistance.

Alternative splicing in plant abiotic stress responses

2020 ◽  
Vol 48 (5) ◽  
pp. 2117-2126
Author(s):  
Paola Punzo ◽  
Stefania Grillo ◽  
Giorgia Batelli
Keyword(s):  
Abiotic Stress ◽  
Alternative Splicing ◽  
Stress Responses ◽  
Environmental Changes ◽  
Single Gene ◽  
Plant Stress ◽  
Protein Isoforms ◽  
Stress Adaptation ◽  
Associated Proteins ◽  
Stress Related Genes

Modifications of the cellular proteome pool upon stress allow plants to tolerate environmental changes. Alternative splicing is the most significant mechanism responsible for the production of multiple protein isoforms from a single gene. The spliceosome, a large ribonucleoprotein complex, together with several associated proteins, controls this pre-mRNA processing, adding an additional level of regulation to gene expression. Deep sequencing of transcriptomes revealed that this co- or post-transcriptional mechanism is highly induced by abiotic stress, and concerns vast numbers of stress-related genes. Confirming the importance of splicing in plant stress adaptation, key players of stress signaling have been shown to encode alternative transcripts, whereas mutants lacking splicing factors or associated components show a modified sensitivity and defective responses to abiotic stress. Here, we examine recent literature on alternative splicing and splicing alterations in response to environmental stresses, focusing on its role in stress adaptation and analyzing the future perspectives and directions for research.

scholarly journals Exploring the functional impact of alternative splicing on human protein isoforms using available annotation sources

2019 ◽  
Vol 20 (5) ◽  
pp. 1754-1768 ◽  
Author(s):  
Dinanath Sulakhe ◽  
Mark D’Souza ◽  
Sheng Wang ◽  
Sandhya Balasubramanian ◽  
Prashanth Athri ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Contextual Information ◽  
Single Gene ◽  
Cellular Responses ◽  
Protein Isoforms ◽  
Modeling And Analysis ◽  
The Public ◽  
Alternatively Spliced ◽  
Cellular Pathways ◽  
Genome Analyses

Abstract In recent years, the emphasis of scientific inquiry has shifted from whole-genome analyses to an understanding of cellular responses specific to tissue, developmental stage or environmental conditions. One of the central mechanisms underlying the diversity and adaptability of the contextual responses is alternative splicing (AS). It enables a single gene to encode multiple isoforms with distinct biological functions. However, to date, the functions of the vast majority of differentially spliced protein isoforms are not known. Integration of genomic, proteomic, functional, phenotypic and contextual information is essential for supporting isoform-based modeling and analysis. Such integrative proteogenomics approaches promise to provide insights into the functions of the alternatively spliced protein isoforms and provide high-confidence hypotheses to be validated experimentally. This manuscript provides a survey of the public databases supporting isoform-based biology. It also presents an overview of the potential global impact of AS on the human canonical gene functions, molecular interactions and cellular pathways.

scholarly journals Alternative RNA splicing in tumour heterogeneity, plasticity and therapy

2022 ◽  
Vol 15 (1) ◽  
Author(s):  
Sebastian Öther-Gee Pohl ◽  
Kevin B. Myant
Keyword(s):  
Alternative Splicing ◽  
Genome Instability ◽  
Single Gene ◽  
Protein Translation ◽  
Response To Therapy ◽  
Protein Isoforms ◽  
Cellular Plasticity ◽  
Tumour Heterogeneity ◽  
In Vivo Models

ABSTRACT Alternative splicing is a process by which a single gene is able to encode multiple different protein isoforms. It is regulated by the inclusion or exclusion of introns and exons that are joined in different patterns prior to protein translation, thus enabling transcriptomic and proteomic diversity. It is now widely accepted that alternative splicing is dysregulated across nearly all cancer types. This widespread dysregulation means that nearly all cellular processes are affected – these include processes synonymous with the hallmarks of cancer – evasion of apoptosis, tissue invasion and metastasis, altered cellular metabolism, genome instability and drug resistance. Emerging evidence indicates that the dysregulation of alternative splicing also promotes a permissive environment for increased tumour heterogeneity and cellular plasticity. These are fundamental regulators of a patient's response to therapy. In this Review, we introduce the mechanisms of alternative splicing and the role of aberrant splicing in cancer, with particular focus on newfound evidence of alternative splicing promoting tumour heterogeneity, cellular plasticity and altered metabolism. We discuss recent in vivo models generated to study alternative splicing and the importance of these for understanding complex tumourigenic processes. Finally, we review the effects of alternative splicing on immune evasion, cell death and genome instability, and how targeting these might enhance therapeutic efficacy.

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