scholarly journals Specific alternative splicing and polyadenylation facilitate metastasis mediated by CTC clusters

2021 ◽  
Author(s):  
Wen Zhang ◽  
Quanyou Wu ◽  
Guoliang Li ◽  
Zhenrong Yang ◽  
Defeng Kong ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Posttranscriptional Regulation ◽  
Alternative Polyadenylation ◽  
Cell Types ◽  
Circulating Tumor Cell ◽  
Rna Regulation ◽  
Regulation Mechanisms ◽  
Specific Alternative ◽  
Single Ctcs

Abstract Circulating tumor cell (CTC) clusters possess a much higher capability to seed metastasis than single CTCs. However, the mechanism underlying this phenomenon is still elusive and no reports have investigated the role of posttranscriptional RNA regulation in CTC clusters. Here, we compared alternative splicing (AS) and alternative polyadenylation (APA) profiles between single CTCs and CTC clusters. 994 and 836 AS events were identified in single CTCs and CTC clusters, separately. About ~20% of AS events exhibited alterations between both cell types. The differential splicing of SRSF6 was a core event that caused AS profiles’ disturbance and made CTC clusters more dangerous. Concerning APA, we identified global 3’ UTRs lengthening in CTC clusters compared with single CTCs. This change was mainly regulated by 14 core APA factors, especially PPP1CA. The altered APA profiles boosted the cell cycle of CTC clusters and reflected that CTC clusters endured less oxidative stress. Our study investigated the posttranscriptional regulation mechanisms in CTC clusters, found that the perturbation of AS and APA contributed to the superiority of CTC clusters compared with single CTCs, and laid the foundation for developing antisense oligonucleotides that inhibit metastasis by reducing CTC clusters.

scholarly journals The Role of Extracellular Vesicles: An Epigenetic View of the Cancer Microenvironment

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Zhongrun Qian ◽  
Qi Shen ◽  
Xi Yang ◽  
Yongming Qiu ◽  
Wenbin Zhang
Keyword(s):  
Extracellular Vesicles ◽  
Immune Cells ◽  
Posttranscriptional Regulation ◽  
Donor Cell ◽  
Cell Types ◽  
Cancer Microenvironment ◽  
Patients With Cancer ◽  
Proliferation And Metastasis ◽  
Extracellular Environment

Exosomes, microvesicles, and other extracellular vesicles are released by many cell types, including cancer cells and cancer-related immune cells. Extracellular vesicles can directly or indirectly facilitate the transfer of bioinformation to recipient cells or to the extracellular environment. In cancer, exosomes have been implicated in tumor initiation, proliferation, and metastasis. Extracellular vesicles can transmit proteins and nucleic acids that participate in DNA methylation, histone modification, and posttranscriptional regulation of RNA. Factors transmitted by extracellular vesicles reflect the donor cell status, and extracellular vesicles derived from tumor cells may be also responsible for altering expression of tumor promoting and tumor suppressing genes in recipient cells. Thus, circulating extracellular vesicles may act as biomarkers of cancer, and detection of these biomarkers may be applied to diagnosis or assessment of prognosis in patients with cancer.

scholarly journals RNA components of the spliceosome regulate tissue- and cancer-specific alternative splicing

2018 ◽  
Author(s):  
Heidi Dvinge ◽  
Jamie Guenthoer ◽  
Peggy L. Porter ◽  
Robert K. Bradley
Keyword(s):  
Alternative Splicing ◽  
Core Protein ◽  
Cancer Cell Line ◽  
Cell Types ◽  
Malignant Cells ◽  
U6 Snrna ◽  
Small Nuclear Rnas ◽  
Order Of Magnitude ◽  
Specific Alternative ◽  
Protein Components

AbstractAlternative splicing of pre-mRNAs plays a pivotal role during the establishment and maintenance of human cell types. Characterizing thetrans-acting regulatory proteins that control alternative splicing in both healthy and malignant cells has therefore been the focus of much research. Recent work has established that even core protein components of the spliceosome, which are required for splicing to proceed, can nonetheless contribute to splicing regulation by modulating splice site choice. We here demonstrate that the RNA components of the spliceosome likewise influence alternative splicing decisions and contribute to the establishment of global splicing programs. Although these small nuclear RNAs (snRNAs), termed U1, U2, U4, U5, and U6 snRNA, are present in equal stoichiometry within the spliceosome, we found that their relative levels vary by an order of magnitude during development, across tissues, and between normal and malignant cells. Physiologically relevant perturbation of individual snRNAs drove widespread gene-specific differences in alternative splicing, but not transcriptome-wide splicing failure. Genes that were particularly sensitive to variations in snRNA abundance in a breast cancer cell line model were likewise preferentially mis-spliced within a clinically diverse cohort of invasive breast ductal carcinomas. As aberrant mRNA splicing is prevalent in many solid and liquid tumors, we propose that a full understanding of dysregulated pre-mRNA processing in cancers requires study of the RNA as well as protein components of the splicing machinery.

scholarly journals Minireview: Global Regulation and Dynamics of Ribonucleic Acid

Endocrinology ◽  
2010 ◽  
Vol 151 (4) ◽  
pp. 1391-1397 ◽  
Author(s):  
Jack D. Keene
Keyword(s):  
Posttranscriptional Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Stability ◽  
Insulin Receptors ◽  
Dynamic Features ◽  
Rna Regulation ◽  
Environmental Signals ◽  
The Many

Gene expression starts with transcription and is followed by multiple posttranscriptional processes that carry out the splicing, capping, polyadenylation, and export of each mRNA. Interest in posttranscriptional regulation has increased recently with explosive discoveries of large numbers of noncoding RNAs such as microRNAs, yet posttranscriptional processes depend largely on the functions of RNA-binding proteins as well. Glucocorticoid nuclear receptors are classical examples of environmentally reactive activators and repressors of transcription, but there has also been a significant increase in studies of the role of posttranscriptional regulation in endocrine responses, including insulin and insulin receptors, and parathyroid hormone as well as other hormonal responses, at the levels of RNA stability and translation. On the global level, the transcriptome is defined as the total RNA complement of the genome, and thereby, represents the accumulated levels of all expressed RNAs, because they are each being produced and eventually degraded in either the nucleus or the cytoplasm. In addition to RNA turnover, the many underlying posttranscriptional layers noted above that follow from the transcriptome function within a dynamic ribonucleoprotein (RNP) environment of global RNA-protein and RNA-RNA interactions. With the exception of the spliceosome and the ribosome, thousands of heterodispersed RNP complexes wherein RNAs are dynamically processed, trafficked, and exchanged are heterogeneous in size and composition, thus providing significant challenges to their investigation. Among the diverse RNPs that show dynamic features in the cytoplasm are processing bodies and stress granules as well as a large number of smaller heterogeneous RNPs distributed throughout the cell. Although the localization of functionally related RNAs within these RNPs are responsive to developmental and environmental signals, recent studies have begun to elucidate the global RNA components of RNPs that are dynamically coordinated in response to these signals. Among the factors that have been found to affect coordinated RNA regulation are developmental signals and treatments with small molecule drugs, hormones, and toxins, but this field is just beginning to understand the role of RNA dynamics in these responses.

SR protein kinases: the splice of life

1999 ◽  
Vol 77 (4) ◽  
pp. 293-298 ◽  
Author(s):  
David F Stojdl ◽  
John C Bell
Keyword(s):  
Alternative Splicing ◽  
Splice Site ◽  
Site Selection ◽  
Developmental Process ◽  
Messenger Rnas ◽  
Splice Site Selection ◽  
Sr Protein ◽  
Specific Alternative ◽  
Mature Mrnas

The eukaryotic genome codes for most of its proteins though discontinuous coding sequences called exons, which are separated by noncoding sequences known as introns. Following transcription of a gene, these exons must be spliced precisely, removing the intervening introns, to form meaningful mature messenger RNAs (mRNA) that are transported to the cytoplasm and translated by the ribosomal machinery. To add yet another level of complexity, a process known as alternative splicing exists, whereby a single pre-mRNA can give rise to two or more mature mRNAs depending on the combination of exons spliced together. Alternative splicing of pre-mRNAs is emerging as an important mechanism for gene regulation in many organisms. The classic example of splicing as a regulator of genetic information during a developmental process is sex determination in Drosophila. The now well-characterized cascade of sex-specific alternative splicing events demonstrates nicely how the control of splice site selection during pre-mRNA processing can have a profound effect on the development of an organism. The factors involved in pre-mRNA splicing and alternative splice site selection have been the subject of active study in recent years. Emerging from these studies is a picture of regulation based on protein-protein, protein-RNA, and RNA-RNA interactions. How the interaction of the various splicing constituents is controlled, however, is still poorly understood. One of the mechanisms of regulation that has received attention recently is that of posttranslational phosphorylation. In the following article, we cite the evidence for a role of phosphorylation in constitutive and alternative splicing and discuss some of the recent information on the biochemistry and biology of the enzymes involved.Key words: phosphorylation, splicing, spliceosome, Clk kinases, SR proteins.

scholarly journals Regulation of Fibronectin EDA Exon Alternative Splicing: Possible Role of RNA Secondary Structure for Enhancer Display

1999 ◽  
Vol 19 (4) ◽  
pp. 2657-2671 ◽  
Author(s):  
Andrés F. Muro ◽  
Massimo Caputi ◽  
Rajalakshmi Pariyarath ◽  
Franco Pagani ◽  
Emanuele Buratti ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Secondary Structure ◽  
Regulatory Region ◽  
Cell Types ◽  
Regulatory Elements ◽  
Base Change ◽  
Significant Feature ◽  
Functional Studies ◽  
Splicing Regulatory Elements

ABSTRACT The fibronectin primary transcript undergoes alternative splicing in three noncoordinated sites: the cassette-type EDA and EDB exons and the more complex IIICS region. We have shown previously that an 81-nucleotide region within the EDA exon is necessary for exon recognition and that this region contains at least two splicing-regulatory elements: a polypurinic enhancer (exonic splicing enhancer [ESE]) and a nearby silencer element (exonic splicing silencer [ESS]). Here, we have analyzed the function of both elements in different cell types. We have mapped the ESS to the nucleotide level, showing that a single base change is sufficient to abolish its function. Testing of the ESE and ESS elements in heterologous exons, individually or as part of the complete EDA regulatory region, showed that only the ESE element is active in different contexts. Functional studies coupled to secondary-structure enzymatic analysis of the EDA exon sequence variants suggest that the role of the ESS element may be exclusively to ensure the proper RNA conformation and raise the possibility that the display of the ESE element in a loop position may represent a significant feature of the exon splicing-regulatory region.

scholarly journals The circadian clock shapes the Arabidopsis transcriptome by regulating alternative splicing and alternative polyadenylation

2020 ◽  
Vol 295 (22) ◽  
pp. 7608-7619 ◽  
Author(s):  
Yuchen Yang ◽  
Yun Li ◽  
Aziz Sancar ◽  
Onur Oztas
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Circadian Clock ◽  
Posttranscriptional Regulation ◽  
Environmental Changes ◽  
Intron Retention ◽  
Regulation Of Gene Expression ◽  
Alternative Polyadenylation ◽  
Genome Wide ◽  
Plant Genes

The circadian clock in plants temporally coordinates biological processes throughout the day, synchronizing gene expression with diurnal environmental changes. Circadian oscillator proteins are known to regulate the expression of clock-controlled plant genes by controlling their transcription. Here, using a high-throughput RNA-Seq approach, we examined genome-wide circadian and diurnal control of the Arabidopsis transcriptome, finding that the oscillation patterns of different transcripts of multitranscript genes can exhibit substantial differences and demonstrating that the circadian clock affects posttranscriptional regulation. In parallel, we found that two major posttranscriptional mechanisms, alternative splicing (AS; especially intron retention) and alternative polyadenylation (APA), display circadian rhythmicity resulting from oscillation in the genes involved in AS and APA. Moreover, AS-related genes exhibited rhythmic AS and APA regulation, adding another layer of complexity to circadian regulation of gene expression. We conclude that the Arabidopsis circadian clock not only controls transcription of genes but also affects their posttranscriptional regulation by influencing alternative splicing and alternative polyadenylation.

scholarly journals Determination of a Comprehensive Alternative Splicing Regulatory Network and Combinatorial Regulation by Key Factors during the Epithelial-to-Mesenchymal Transition

2016 ◽  
Vol 36 (11) ◽  
pp. 1704-1719 ◽  
Author(s):  
Yueqin Yang ◽  
Juw Won Park ◽  
Thomas W. Bebee ◽  
Claude C. Warzecha ◽  
Yang Guo ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Regulatory Network ◽  
Posttranscriptional Regulation ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Combinatorial Regulation ◽  
Mesenchymal Transition ◽  
Splicing Regulators

The epithelial-to-mesenchymal transition (EMT) is an essential biological process during embryonic development that is also implicated in cancer metastasis. While the transcriptional regulation of EMT has been well studied, the role of alternative splicing (AS) regulation in EMT remains relatively uncharacterized. We previously showed that the epithelial cell-type-specific proteinsepithelialsplicingregulatoryproteins 1 (ESRP1) and ESRP2 are important for the regulation of many AS events that are altered during EMT. However, the contributions of the ESRPs and other splicing regulators to the AS regulatory network in EMT require further investigation. Here, we used a robustin vitroEMT model to comprehensively characterize splicing switches during EMT in a temporal manner. These investigations revealed that the ESRPs are the major regulators of some but not all AS events during EMT. We determined that the splicing factor RBM47 is downregulated during EMT and also regulates numerous transcripts that switch splicing during EMT. We also determined that Quaking (QKI) broadly promotes mesenchymal splicing patterns. Our study highlights the broad role of posttranscriptional regulation during the EMT and the important role of combinatorial regulation by different splicing factors to fine tune gene expression programs during these physiological and developmental transitions.

Effect of Calcium on the Growth and Differentiation of Cultured Rat Esophageal Epithelial Cells

1982 ◽  
Vol 40 ◽  
pp. 132-133
Author(s):  
W.T. Gunning ◽  
M.R. Marino ◽  
M.S. Babcock ◽  
G.D. Stoner
Keyword(s):  
Epithelial Cells ◽  
Cell Types ◽  
Replication Rate ◽  
Enzymatic Dissociation ◽  
Growth Assay ◽  
Epidermal Growth ◽  
Fetal Bovine ◽  
Esophageal Epithelial Cells ◽  
Cellular Replication

The role of calcium in modulating cellular replication and differentiation has been described for various cell types. In the present study, the effects of Ca++ on the growth and differentiation of cultured rat esophageal epithelial cells was investigated.Epithelial cells were isolated from esophagi taken from 8 week-old male CDF rats by the enzymatic dissociation method of Kaighn. The cells were cultured in PFMR-4 medium supplemented with 0.25 mg/ml dialyzed fetal bovine serum, 5 ng/ml epidermal growth factor, 10-6 M hydrocortisone 10-6 M phosphoethanolamine, 10-6 M ethanolamine, 5 pg/ml insulin, 5 ng/ml transferrin, 10 ng/ml cholera toxin and 50 ng/ml garamycin at 36.5°C in a humidified atmosphere of 3% CO2 in air. At weekly intervals, the cells were subcultured with a solution containing 1% polyvinylpyrrolidone, 0.01% EGTA, and 0.05% trypsin. After various passages, the replication rate of the cells in PFMR-4 medium containing from 10-6 M to 10-3 M Ca++ was determined using a clonal growth assay.

Role of PKC isozymes in water transport in toad urinary bladder

1991 ◽  
Vol 49 ◽  
pp. 302-303
Author(s):  
A.J. Mia ◽  
L.X. Oakford ◽  
T. Yorio
Keyword(s):  
Urinary Bladder ◽  
Apical Membrane ◽  
Membrane Surface ◽  
Protein A ◽  
Cell Types ◽  
Leukemic Cells ◽  
Toad Urinary Bladder ◽  
Pkc Isozymes ◽  
Antibody Labeling

Protein kinase C (PKC) isozymes, when activated, are translocated to particulate membrane fractions for transport to the apical membrane surface in a variety of cell types. Evidence of PKC translocation was demonstrated in human megakaryoblastic leukemic cells, and in cardiac myocytes and fibroblasts, using FTTC immunofluorescent antibody labeling techniques. Recently, we reported immunogold localizations of PKC subtypes I and II in toad urinary bladder epithelia, following 60 min stimulation with Mezerein (MZ), a PKC activator, or antidiuretic hormone (ADH). Localization of isozyme subtypes I and n was carried out in separate grids using specific monoclonal antibodies with subsequent labeling with 20nm protein A-gold probes. Each PKC subtype was found to be distributed singularly and in discrete isolated patches in the cytosol as well as in the apical membrane domains. To determine if the PKC isozymes co-localized within the cell, a double immunogold labeling technique using single grids was utilized.

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