scholarly journals Phosphorylation-Mediated Regulation of Alternative Splicing in Cancer

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Chiara Naro ◽  
Claudio Sette
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Posttranslational Modifications ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Splice Variants ◽  
Single Gene ◽  
Regulation Of Gene Expression ◽  
Eukaryotic Cells ◽  
Macromolecular Complex

Alternative splicing (AS) is one of the key processes involved in the regulation of gene expression in eukaryotic cells. AS catalyzes the removal of intronic sequences and the joining of selected exons, thus ensuring the correct processing of the primary transcript into the mature mRNA. The combinatorial nature of AS allows a great expansion of the genome coding potential, as multiple splice-variants encoding for different proteins may arise from a single gene. Splicing is mediated by a large macromolecular complex, the spliceosome, whose activity needs a fine regulation exerted bycis-acting RNA sequence elements andtrans-acting RNA binding proteins (RBP). The activity of both core spliceosomal components and accessory splicing factors is modulated by their reversible phosphorylation. The kinases and phosphatases involved in these posttranslational modifications significantly contribute to AS regulation and to its integration in the complex regulative network that controls gene expression in eukaryotic cells. Herein, we will review the major canonical and noncanonical splicing factor kinases and phosphatases, focusing on those whose activity has been implicated in the aberrant splicing events that characterize neoplastic transformation.

scholarly journals Position Specific Alternative Splicing and Gene Expression Profiles Along the Tonotopic Axis of Chick Cochlea

2021 ◽  
Vol 8 ◽  
Author(s):  
Heiyeun Koo ◽  
Jae Yeon Hwang ◽  
Sungbo Jung ◽  
Hyeyoung Park ◽  
Jinwoong Bok ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Expression Profiles ◽  
Single Gene ◽  
Gene Expression Profiles ◽  
Binding Motif ◽  
Dependent Manner ◽  
Mrna Isoforms

Alternative splicing (AS) refers to the production of multiple mRNA isoforms from a single gene due to alternative selection of exons or splice sites during pre-mRNA splicing. It is a primary mechanism of gene regulation in higher eukaryotes and significantly expands the functional complexity of eukaryotic organisms, contributing to animal development and disease. Recent studies have shown that AS also influences functional diversity by affecting the transcriptomic and proteomic profiles in a position-dependent manner in a single organ. The peripheral hearing organ, the cochlea, is organized to detect sounds at different frequencies depending on its location along the longitudinal axis. This unique functional configuration, the tonotopy, is known to be facilitated by differential gene expression along the cochlear duct. We profiled transcriptome-wide gene expression and AS changes that occur within the different positions of chick cochlea. These analyses revealed distinct gene expression profiles and AS, including a splicing program that is unique to tonotopy. Changes in the expression of splicing factors PTBP3, ESRP1, and ESRP2 were demonstrated to contribute to position-specific AS. RNA-binding motif enrichment analysis near alternatively spliced exons provided further insight into the combinatorial regulation of AS at different positions by different RNA-binding proteins. These data, along with gene ontology (GO) analysis, represent a comprehensive analysis of the dynamic regulation of AS at different positions in chick cochlea.

scholarly journals Differentially expressed IGF2BP2 in ovarian disorders: strongly associates with alternative splicing regulation in human granulosa cells

2021 ◽  
Author(s):  
Feiyan Zhao ◽  
Qin Wang ◽  
Tong Chen ◽  
Xuehan Zhao ◽  
Zhimin Xin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Granulosa Cells ◽  
Target Genes ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Follicular Development ◽  
Endocrine Disorders ◽  
Human Granulosa Cells

Abstract Genome-wide interactions between RNA-binding proteins (RBPs) and RNA targets account for an important portion of post-transcriptional regulation. IGF2BP2 is associated with type 2 diabetes (T2D) and obesity and reportedly functions as an RBP that regulates a series of target genes by binding RNA transcripts. In this study, we detected the differential expression of IGF2BP2 in granulosa cells from women with ovarian disorders and performed RNA-seq and RIP-seq experiments in immortalized human granulosa cells (KGN cells) to evaluate global transcript levels and alternative splicing on KGN cells overexpressing IGF2BP2 versus controls. Our results show that IGF2BP2 preferentially binds to the 3’and 5’UTRs of mRNAs and enriches target gene expression in KGN cells. Notably, besides the conventional GGAC motif, we found a significant enrichment of a new GAAG motif within IGF2BP2-binding regions. We demonstrate that IGF2BP2 is involved in transcription regulation and alternative splicing in genes associated with follicular development. Furthermore, IGF2BP2 partly influences the expression levels of some of these alternatively spliced genes, including MBD3 and FN1, which may lead to ovarian endocrine disorders. In conclusion, we provide a transcriptome-wide analysis that demonstrates the role played by IGF2BP2 in the regulation of gene expression, transcription and alternative splicing of a number of genes involved in the pathogenesis of ovarian endocrine diseases.

Linking transcription, RNA polymerase II elongation and alternative splicing

2020 ◽  
Vol 477 (16) ◽  
pp. 3091-3104 ◽  
Author(s):  
Luciana E. Giono ◽  
Alberto R. Kornblihtt
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Rna Polymerase Ii ◽  
Environmental Changes ◽  
Transcription Elongation ◽  
Single Gene ◽  
Regulation Of Gene Expression ◽  
Regulation Of Transcription ◽  
Stepping Stones ◽  
Eukaryotic Transcription

Gene expression is an intricately regulated process that is at the basis of cell differentiation, the maintenance of cell identity and the cellular responses to environmental changes. Alternative splicing, the process by which multiple functionally distinct transcripts are generated from a single gene, is one of the main mechanisms that contribute to expand the coding capacity of genomes and help explain the level of complexity achieved by higher organisms. Eukaryotic transcription is subject to multiple layers of regulation both intrinsic — such as promoter structure — and dynamic, allowing the cell to respond to internal and external signals. Similarly, alternative splicing choices are affected by all of these aspects, mainly through the regulation of transcription elongation, making it a regulatory knob on a par with the regulation of gene expression levels. This review aims to recapitulate some of the history and stepping-stones that led to the paradigms held today about transcription and splicing regulation, with major focus on transcription elongation and its effect on alternative splicing.

scholarly journals Coordination of RNA Processing Regulation by Signal Transduction Pathways

Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1475
Author(s):  
Veronica Ruta ◽  
Vittoria Pagliarini ◽  
Claudio Sette
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Rna Processing ◽  
Translational Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Signal Transduction Pathways ◽  
Challenges And Opportunities ◽  
Common Signal

Signal transduction pathways transmit the information received from external and internal cues and generate a response that allows the cell to adapt to changes in the surrounding environment. Signaling pathways trigger rapid responses by changing the activity or localization of existing molecules, as well as long-term responses that require the activation of gene expression programs. All steps involved in the regulation of gene expression, from transcription to processing and utilization of new transcripts, are modulated by multiple signal transduction pathways. This review provides a broad overview of the post-translational regulation of factors involved in RNA processing events by signal transduction pathways, with particular focus on the regulation of pre-mRNA splicing, cleavage and polyadenylation. The effects of several post-translational modifications (i.e., sumoylation, ubiquitination, methylation, acetylation and phosphorylation) on the expression, subcellular localization, stability and affinity for RNA and protein partners of many RNA-binding proteins are highlighted. Moreover, examples of how some of the most common signal transduction pathways can modulate biological processes through changes in RNA processing regulation are illustrated. Lastly, we discuss challenges and opportunities of therapeutic approaches that correct RNA processing defects and target signaling molecules.

scholarly journals CELF RNA binding proteins promote axon regeneration in C. elegans and mammals through alternative splicing of Syntaxins

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lizhen Chen ◽  
Zhijie Liu ◽  
Bing Zhou ◽  
Chaoliang Wei ◽  
Yu Zhou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Alternative Splicing ◽  
Binding Proteins ◽  
Rna Binding ◽  
Axon Regeneration ◽  
Rna Binding Proteins ◽  
Mrna Isoforms ◽  
C Elegans ◽  
Mrna Targets

Axon injury triggers dramatic changes in gene expression. While transcriptional regulation of injury-induced gene expression is widely studied, less is known about the roles of RNA binding proteins (RBPs) in post-transcriptional regulation during axon regeneration. In C. elegans the CELF (CUGBP and Etr-3 Like Factor) family RBP UNC-75 is required for axon regeneration. Using crosslinking immunoprecipitation coupled with deep sequencing (CLIP-seq) we identify a set of genes involved in synaptic transmission as mRNA targets of UNC-75. In particular, we show that UNC-75 regulates alternative splicing of two mRNA isoforms of the SNARE Syntaxin/unc-64. In C. elegans mutants lacking unc-75 or its targets, regenerating axons form growth cones, yet are deficient in extension. Extending these findings to mammalian axon regeneration, we show that mouse Celf2 expression is upregulated after peripheral nerve injury and that Celf2 mutant mice are defective in axon regeneration. Further, mRNAs for several Syntaxins show CELF2 dependent regulation. Our data delineate a post-transcriptional regulatory pathway with a conserved role in regenerative axon extension.

scholarly journals Characterization of Conserved Tandem Donor Sites and Intronic Motifs Required for Alternative Splicing in Corticosteroid Receptor Genes

Endocrinology ◽  
2009 ◽  
Vol 150 (11) ◽  
pp. 4958-4967 ◽  
Author(s):  
Caroline Rivers ◽  
Andrea Flynn ◽  
Xiaoxiao Qian ◽  
Laura Matthews ◽  
Stafford Lightman ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Splice Site ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Splice Variants ◽  
Mammalian Species ◽  
Donor Site ◽  
Small Nuclear Rna ◽  
Endogenous Gene ◽  
The One

Alternative splicing events from tandem donor sites result in mRNA variants coding for additional amino acids in the DNA binding domain of both the glucocorticoid (GR) and mineralocorticoid (MR) receptors. We now show that expression of both splice variants is extensively conserved in mammalian species, providing strong evidence for their functional significance. An exception to the conservation of the MR tandem splice site (an A at position +5 of the MR+12 donor site in the mouse) was predicted to decrease U1 small nuclear RNA binding. In accord with this prediction, we were unable to detect the MR+12 variant in this species. The one exception to the conservation of the GR tandem splice site, an A at position +3 of the platypus GRγ donor site that was predicted to enhance binding of U1 snRNA, was unexpectedly associated with decreased expression of the variant from the endogenous gene as well as a minigene. An intronic pyrimidine motif present in both GR and MR genes was found to be critical for usage of the downstream donor site, and overexpression of TIA1/TIAL1 RNA binding proteins, which are known to bind such motifs, led to a marked increase in the proportion of GRγ and MR+12. These results provide striking evidence for conservation of a complex splicing mechanism that involves processes other than stochastic spliceosome binding and identify a mechanism that would allow regulation of variant expression.

scholarly journals RNA-Binding Proteins as Regulators of Migration, Invasion and Metastasis in Oral Squamous Cell Carcinoma

2020 ◽  
Vol 21 (18) ◽  
pp. 6835
Author(s):  
Jonas Weiße ◽  
Julia Rosemann ◽  
Vanessa Krauspe ◽  
Matthias Kappler ◽  
Alexander W. Eckert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Invasion And Metastasis ◽  
Protein Coding ◽  
Oral Cancers ◽  
Cellular Processes ◽  
Post Transcriptional Regulation

Nearly 7.5% of all human protein-coding genes have been assigned to the class of RNA-binding proteins (RBPs), and over the past decade, RBPs have been increasingly recognized as important regulators of molecular and cellular homeostasis. RBPs regulate the post-transcriptional processing of their target RNAs, i.e., alternative splicing, polyadenylation, stability and turnover, localization, or translation as well as editing and chemical modification, thereby tuning gene expression programs of diverse cellular processes such as cell survival and malignant spread. Importantly, metastases are the major cause of cancer-associated deaths in general, and particularly in oral cancers, which account for 2% of the global cancer mortality. However, the roles and architecture of RBPs and RBP-controlled expression networks during the diverse steps of the metastatic cascade are only incompletely understood. In this review, we will offer a brief overview about RBPs and their general contribution to post-transcriptional regulation of gene expression. Subsequently, we will highlight selected examples of RBPs that have been shown to play a role in oral cancer cell migration, invasion, and metastasis. Last but not least, we will present targeting strategies that have been developed to interfere with the function of some of these RBPs.

scholarly journals The Tristetraprolin Family of RNA-Binding Proteins in Cancer: Progress and Future Prospects

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1539 ◽  
Author(s):  
Yogesh Saini ◽  
Jian Chen ◽  
Sonika Patial
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Zinc Finger ◽  
Binding Proteins ◽  
Rna Binding ◽  
Zinc Finger Protein ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Finger Protein ◽  
Post Transcriptional Regulation

Post-transcriptional regulation of gene expression plays a key role in cellular proliferation, differentiation, migration, and apoptosis. Increasing evidence suggests dysregulated post-transcriptional gene expression as an important mechanism in the pathogenesis of cancer. The tristetraprolin family of RNA-binding proteins (RBPs), which include Zinc Finger Protein 36 (ZFP36; commonly referred to as tristetraprolin (TTP)), Zinc Finger Protein 36 like 1 (ZFP36L1), and Zinc Finger Protein 36 like 2 (ZFP36L2), play key roles in the post-transcriptional regulation of gene expression. Mechanistically, these proteins function by binding to the AU-rich elements within the 3′-untranslated regions of their target mRNAs and, in turn, increasing mRNA turnover. The TTP family RBPs are emerging as key regulators of multiple biological processes relevant to cancer and are aberrantly expressed in numerous human cancers. The TTP family RBPs have tumor-suppressive properties and are also associated with cancer prognosis, metastasis, and resistance to chemotherapy. Herein, we summarize the various hallmark molecular traits of cancers that are reported to be regulated by the TTP family RBPs. We emphasize the role of the TTP family RBPs in the regulation of trait-associated mRNA targets in relevant cancer types/cell lines. Finally, we highlight the potential of the TTP family RBPs as prognostic indicators and discuss the possibility of targeting these TTP family RBPs for therapeutic benefits.

scholarly journals Perspective in Alternative Splicing Coupled to Nonsense-Mediated mRNA Decay

2020 ◽  
Vol 21 (24) ◽  
pp. 9424
Author(s):  
Juan F. García-Moreno ◽  
Luísa Romão
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Translation Termination ◽  
Mrna Isoforms ◽  
Isoform Diversity ◽  
Nonsense Mediated Mrna Decay ◽  
Protein Isoform ◽  
Nonsense Mediated Rna Decay

Alternative splicing (AS) of precursor mRNA (pre-mRNA) is a cellular post-transcriptional process that generates protein isoform diversity. Nonsense-mediated RNA decay (NMD) is an mRNA surveillance pathway that recognizes and selectively degrades transcripts containing premature translation-termination codons (PTCs), thereby preventing the production of truncated proteins. Nevertheless, NMD also fine-tunes the gene expression of physiological mRNAs encoding full-length proteins. Interestingly, around one third of all AS events results in PTC-containing transcripts that undergo NMD. Numerous studies have reported a coordinated action between AS and NMD, in order to regulate the expression of several genes, especially those coding for RNA-binding proteins (RBPs). This coupling of AS to NMD (AS-NMD) is considered a gene expression tool that controls the ratio of productive to unproductive mRNA isoforms, ultimately degrading PTC-containing non-functional mRNAs. In this review, we focus on the mechanisms underlying AS-NMD, and how this regulatory process is able to control the homeostatic expression of numerous RBPs, including splicing factors, through auto- and cross-regulatory feedback loops. Furthermore, we discuss the importance of AS-NMD in the regulation of biological processes, such as cell differentiation. Finally, we analyze interesting recent data on the relevance of AS-NMD to human health, covering its potential roles in cancer and other disorders.

scholarly journals Dynamic mRNP Remodeling in Response to Internal and External Stimuli

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1310 ◽  
Author(s):  
Kathi Zarnack ◽  
Sureshkumar Balasubramanian ◽  
Michael P. Gantier ◽  
Vladislav Kunetsky ◽  
Michael Kracht ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Rna Binding ◽  
Environmental Changes ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Cellular Processes ◽  
Messenger Ribonucleoprotein ◽  
Transcriptional Modulation ◽  
External Stimuli

Signal transduction and the regulation of gene expression are fundamental processes in every cell. RNA-binding proteins (RBPs) play a key role in the post-transcriptional modulation of gene expression in response to both internal and external stimuli. However, how signaling pathways regulate the assembly of RBPs with mRNAs remains largely unknown. Here, we summarize observations showing that the formation and composition of messenger ribonucleoprotein particles (mRNPs) is dynamically remodeled in space and time by specific signaling cascades and the resulting post-translational modifications. The integration of signaling events with gene expression is key to the rapid adaptation of cells to environmental changes and stress. Only a combined approach analyzing the signal transduction pathways and the changes in post-transcriptional gene expression they cause will unravel the mechanisms coordinating these important cellular processes.

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