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 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 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 Alternative REST Splicing Underappreciated

2017 ◽  
Author(s):  
Guo-Lin Chen ◽  
Gregory M. Miller
Keyword(s):  
Alternative Splicing ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Protein Isoforms ◽  
Multiple Protein ◽  
Mrna Variants ◽  
Cellular Context ◽  
Active Transcription ◽  
Context Dependent ◽  
Ageing Brain

As a major orchestrator of the cellular epigenome, the repressor element-1 silencing transcription factor (REST) can either repress or activate thousands of genes depending on cellular context, suggesting a highly context-dependent REST function tuned by environmental cues. While REST shows cell-type non-selective active transcription1, an N-terminal REST4 isoform caused by alternative splicing – inclusion of an extra exon (N3c) which introduces a premature stop codon – has been implicated in neurogenesis and tumorigenesis2-5. Recently, in line with established epigenetic regulation of pre-mRNA splicing6,7, we demonstrated that REST undergoes extensive, context-dependent alternative splicing which results in the formation of a large number of mRNA variants predictive of multiple protein isoforms8. Supported by that immunoblotting/-staining with different anti-REST antibodies yield inconsistent results, alternative splicing allows production of various structurally and functionally different REST protein isoforms in response to shifting physiological requirements, providing a reasonable explanation for the diverse, highly context-dependent REST function. However, REST isoforms might be differentially assayed or manipulated, leading to data misinterpretation and controversial findings. For example, in contrast to the proposed neurotoxicity of elevated nuclear REST in ischemia9 and Huntington’s disease10,11, Lu et al. recently reported decreased nuclear REST in Alzheimer’s disease and neuroprotection of REST in ageing brain12. Unfortunately, alternative REST splicing was largely neglected by Lu et al., making it necessary for a reevaluation of their findings.

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.

scholarly journals Regulation of FXR1 by alternative splicing is required for muscle development and controls liquid-like condensates in muscle cells

2019 ◽  
Author(s):  
Jean A. Smith ◽  
Ennessa G. Curry ◽  
R. Eric Blue ◽  
Christine Roden ◽  
Samantha E. R. Dundon ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Muscle Development ◽  
Rna Binding ◽  
Fragile X ◽  
Protein Isoforms ◽  
List Type ◽  
Tissue Specific ◽  
Intrinsically Disordered ◽  
Multiple Protein

SUMMARYFragile-X mental retardation autosomal homolog-1 (FXR1) is a muscle-enriched RNA-binding protein. FXR1 depletion is perinatally lethal in mice, Xenopus, and zebrafish; however, the mechanisms driving these phenotypes remain unclear. The FXR1 gene undergoes alternative splicing, producing multiple protein isoforms and mis-splicing has been implicated in disease. Furthermore, mutations that cause frameshifts in muscle-specific isoforms result in congenital multi-minicore myopathy. We observed that FXR1 alternative splicing is pronounced in the serine and arginine-rich intrinsically-disordered domain; these domains are known to promote biomolecular condensation. Here, we show that tissue-specific splicing of fxr1 is required for Xenopus development and alters the disordered domain of FXR1. FXR1 isoforms vary in the formation of RNA-dependent biomolecular condensates in cells and in vitro. This work shows that regulation of tissue-specific splicing can influence FXR1 condensates in muscle development and how mis-splicing promotes disease.HIGHLIGHTSThe muscle-specific exon 15 impacts FXR1 functionsAlternative splicing of FXR1 is tissue- and developmental stage specificFXR1 forms RNA-dependent condensatesSplicing regulation changes FXR1 condensate properties

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.

Substances that can change alternative splice-site selection

2008 ◽  
Vol 36 (3) ◽  
pp. 483-490 ◽  
Author(s):  
Chiranthani Sumanasekera ◽  
David S. Watt ◽  
Stefan Stamm
Keyword(s):  
Molecular Mass ◽  
Histone Deacetylases ◽  
Single Gene ◽  
Mrna Splicing ◽  
Protein Isoforms ◽  
Splice Site Selection ◽  
Protein Coding ◽  
Multiple Protein ◽  
Eukaryotic Gene ◽  
Selection Of

Alternative pre-mRNA splicing is an important element in eukaryotic gene expression, as most of the protein-coding genes use this process to generate multiple protein isoforms from a single gene. An increasing number of human diseases are now recognized to be caused by the selection of ‘wrong’ alternative exons. Research during the last few years identified a number of low–molecular-mass chemical substances that can change alternative exon usage. Most of these substances act by either blocking histone deacetylases or by interfering with the phosphorylation of splicing factors. How the remaining large number of these substances affect splicing is not yet fully understood. The emergence of these low-molecular-mass substances provides not only probes for studying alternative pre-mRNA splicing, but also opens the door to the possible harnessing of these compounds as drugs to control diseases caused by the selection of ‘wrong’ splice sites.

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.

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