scholarly journals Alternative Splicing: Recent Insights into Mechanisms and Functional Roles

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2327
Author(s):  
Claudia Ghigna ◽  
Maria Paola Paronetto
Keyword(s):  
Alternative Splicing ◽  
Human Cells ◽  
Protein Isoforms ◽  
Primary Transcript ◽  
Functional Roles ◽  
Multiple Protein

Alternative splicing generates multiple protein isoforms from one primary transcript and represents one of the major drivers of proteomic diversity in human cells [...]

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 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.

Alternative Splicing: A Ubiquitous Mechanism for the Generation of Multiple Protein Isoforms from Single Genes

1987 ◽  
Vol 56 (1) ◽  
pp. 467-495 ◽  
Author(s):  
R E Breitbart ◽  
A Andreadis ◽  
B Nadal-Ginard
Keyword(s):  
Alternative Splicing ◽  
Protein Isoforms ◽  
Multiple Protein

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

Expression of glucocorticoid receptor α- and β-isoforms in human cells and tissues

2002 ◽  
Vol 283 (4) ◽  
pp. C1324-C1331 ◽  
Author(s):  
Laura Pujols ◽  
Joaquim Mullol ◽  
Jordi Roca-Ferrer ◽  
Alfons Torrego ◽  
Antoni Xaubet ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Alternative Splicing ◽  
Glucocorticoid Receptor ◽  
Nasal Mucosa ◽  
Mononuclear Cells ◽  
Human Cells ◽  
Protein Isoforms ◽  
Healthy Human ◽  
Peripheral Blood Mononuclear ◽  
Total Rna

Alternative splicing of the human glucocorticoid receptor (GR) primary transcript generates two protein isoforms: GR-α and GR-β. We investigated the expression of both GR isoforms in healthy human cells and tissues. GR-α mRNA abundance (×106 cDNA copies/μg total RNA) was as follows: brain (3.83 ± 0.80) > skeletal muscle > macrophages > lung > kidney > liver > heart > eosinophils > peripheral blood mononuclear cells (PBMCs) > nasal mucosa > neutrophils > colon (0.33 ± 0.04). GR-β mRNA was much less expressed than GR-α mRNA. Its abundance (×103 cDNA copies/μg total RNA) was as follows: eosinophils (1.55 ± 0.58) > PBMCs > liver ≥ skeletal muscle > kidney > macrophages > lung > neutrophils > brain ≥ nasal mucosa > heart (0.15 ± 0.08). GR-β mRNA was not found in colon. While GR-α protein was detected in all cells and tissues, GR-β was not detected in any specimen. Our results suggest that, in physiological conditions, the default splicing pathway is the one leading to GR-α. The alternative splicing event leading to GR-β is minimally activated.

scholarly journals The putative ovarian tumour marker gene HE4 (WFDC2), is expressed in normal tissues and undergoes complex alternative splicing to yield multiple protein isoforms

Oncogene ◽  
2002 ◽  
Vol 21 (17) ◽  
pp. 2768-2773 ◽  
Author(s):  
Lynne Bingle ◽  
Vanessa Singleton ◽  
Colin D Bingle
Keyword(s):  
Alternative Splicing ◽  
Marker Gene ◽  
Tumour Marker ◽  
Ovarian Tumour ◽  
Protein Isoforms ◽  
Normal Tissues ◽  
Multiple Protein

scholarly journals Alternative Splicing Variants of IκBβ Establish Differential NF-κB Signal Responsiveness in Human Cells

1998 ◽  
Vol 18 (5) ◽  
pp. 2596-2607 ◽  
Author(s):  
Fuminori Hirano ◽  
Mirra Chung ◽  
Hirotoshi Tanaka ◽  
Naoki Maruyama ◽  
Isao Makino ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Rna Processing ◽  
Abundant Species ◽  
Human Cells ◽  
Protein Isoforms ◽  
Activation Mechanism ◽  
Proteolytic Degradation ◽  
Phosphorylation Sites ◽  
Splicing Variants ◽  
Carboxy Terminal

ABSTRACT To release transcription factor NF-κB into the nucleus, the mammalian IκB molecules IκBα and IκBβ are inactivated by phosphorylation and proteolytic degradation. Both proteins contain conserved signal-responsive phosphorylation sites and have conserved ankyrin repeats. To confer specific physiological functions to members of the NF-κB/Rel family, the different IκB molecules could vary in their specific NF-κB/Rel factor binding activities and could respond differently to activation signals. We have demonstrated that both mechanisms apply to differential regulation of NF-κB function by IκBβ relative to IκBα. Via alternative RNA processing, human IκBβ gives rise to different protein isoforms. IκBβ1 and IκBβ2, the major forms in human cells, differ in their carboxy-terminal PEST sequences. IκBβ2 is the most abundant species in a number of human cell lines tested, whereas IκBβ1 is the only form detected in murine cells. These isoforms are indistinguishable in their binding preferences to cellular NF-κB/Rel homo- and heterodimers, which are distinct from those of IκBα, and both are constitutively phosphorylated. In unstimulated B cells, however, IκBβ1, but not IκBβ2, is found in the nucleus. Furthermore, the two forms differ markedly in their efficiency of proteolytic degradation after stimulation with several inducing agents tested. While IκBβ1 is nearly as responsive as IκBα, indicative of a shared activation mechanism, IκBβ2 is only weakly degraded and often not responsive at all. Alternative splicing of the IκBβ pre-mRNA may thus provide a means to selectively control the amount of IκBβ-bound NF-κB heteromers to be released under NF-κB stimulating conditions.

scholarly journals FXR1 splicing is important for muscle development and biomolecular condensates in muscle cells

2020 ◽  
Vol 219 (4) ◽  
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 ◽  
Tissue Specific ◽  
Intrinsically Disordered ◽  
Fragile X Mental Retardation ◽  
Multiple Protein

Fragile-X mental retardation autosomal homologue-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.

scholarly journals Genetic and molecular analysis of an allelic series of cop1 mutants suggests functional roles for the multiple protein domains.

1994 ◽  
Vol 6 (4) ◽  
pp. 487-500 ◽  
Author(s):  
T W McNellis ◽  
A G von Arnim ◽  
T Araki ◽  
Y Komeda ◽  
S Miséra ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Protein Domains ◽  
Allelic Series ◽  
Functional Roles ◽  
Multiple Protein

scholarly journals Identification of prognostic alternative splicing events in sarcoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hongshuai Li ◽  
Jie Yang ◽  
Guohui Yang ◽  
Jia Ren ◽  
Yu Meng ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Cox Regression ◽  
Univariate Analysis ◽  
Area Under The Curve ◽  
Gene Signature ◽  
The Cancer Genome Atlas ◽  
Cox Regression Analysis ◽  
Functional Roles ◽  
Cancer Pathogenesis ◽  
Rare Malignancy

AbstractSarcoma is a rare malignancy with unfavorable prognoses. Accumulating evidence indicates that aberrant alternative splicing (AS) events are generally involved in cancer pathogenesis. The aim of this study was to identify the prognostic value of AS-related survival genes as potential biomarkers, and highlight the functional roles of AS events in sarcoma. RNA-sequencing and AS-event datasets were downloaded from The Cancer Genome Atlas (TCGA) sarcoma cohort and TCGA SpliceSeq, respectively. Survival-related AS events were further assessed using a univariate analysis. A multivariate Cox regression analysis was also performed to establish a survival-gene signature to predict patient survival, and the area-under-the-curve method was used to evaluate prognostic reliability. KOBAS 3.0 and Cytoscape were used to functionally annotate AS-related genes and to assess their network interactions. We detected 9674 AS events in 40,184 genes from 236 sarcoma samples, and the 15 most significant genes were then used to construct a survival regression model. We further validated the involvement of ten potential survival-related genes (TUBB3, TRIM69, ZNFX1, VAV1, KCNN2, VGLL3, AK7, ARMC4, LRRC1, and CRIP1) in the occurrence and development of sarcoma. Multivariate survival model analyses were also performed, and validated that a model using these ten genes provided good classifications for predicting patient outcomes. The present study has increased our understanding of AS events in sarcoma, and the gene-based model using AS-related events may serve as a potential predictor to determine the survival of sarcoma patients.

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