Complexity of COX-2 gene regulation

2008 ◽  
Vol 36 (3) ◽  
pp. 543-545 ◽  
Author(s):  
Kelly A. Harper ◽  
Alison J. Tyson-Capper
Keyword(s):  
Gene Regulation ◽  
Mrna Stability ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Preterm Labour ◽  
Inflammatory Diseases ◽  
Alternative Polyadenylation ◽  
Regulatory Elements ◽  
Translational Efficiency ◽  
Cox 2

Overexpression of the enzyme COX-2 (cyclo-oxygenase-2) is associated with various pathophysiological conditions, including inflammatory diseases and different cancers. Increased synthesis of COX-2 in fetal membranes and the myometrium is also linked with the onset of term and preterm labour. COX-2 gene regulation is controlled at various levels including gene transcription and post-transcriptional events. The present article focuses on the complexity of COX-2 gene regulation and reviews current concepts that highlight: (i) transcription of COX-2 is induced rapidly and transiently in response to a plethora of stimuli; (ii) COX-2 mRNA stability and translational efficiency is governed by multiple regulatory elements within the 3′-untranslated region; (iii) specific microRNAs and RNA-binding proteins influence COX-2 mRNA stability; and (iv) regulation of COX-2 involves alternative polyadenylation.

scholarly journals Alternative polyadenylation: methods, mechanism, function, and role in cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Yi Zhang ◽  
Lian Liu ◽  
Qiongzi Qiu ◽  
Qing Zhou ◽  
Jinwang Ding ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Single Gene ◽  
Alternative Polyadenylation ◽  
Length Change ◽  
Suppressor Gene ◽  
Gene Expressions ◽  
Related Factors ◽  
Mrna Maturation

AbstractOccurring in over 60% of human genes, alternative polyadenylation (APA) results in numerous transcripts with differing 3’ends, thus greatly expanding the diversity of mRNAs and of proteins derived from a single gene. As a key molecular mechanism, APA is involved in various gene regulation steps including mRNA maturation, mRNA stability, cellular RNA decay, and protein diversification. APA is frequently dysregulated in cancers leading to changes in oncogenes and tumor suppressor gene expressions. Recent studies have revealed various APA regulatory mechanisms that promote the development and progression of a number of human diseases, including cancer. Here, we provide an overview of four types of APA and their impacts on gene regulation. We focus particularly on the interaction of APA with microRNAs, RNA binding proteins and other related factors, the core pre-mRNA 3’end processing complex, and 3’UTR length change. We also describe next-generation sequencing methods and computational tools for use in poly(A) signal detection and APA repositories and databases. Finally, we summarize the current understanding of APA in cancer and provide our vision for future APA related research.

scholarly journals Inflammation-regulated mRNA stability and the progression of vascular inflammatory diseases

2017 ◽  
Vol 131 (22) ◽  
pp. 2687-2699 ◽  
Author(s):  
Allison B. Herman ◽  
Michael V. Autieri
Keyword(s):  
Mrna Stability ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Inflammatory Diseases ◽  
Inflammatory Cells ◽  
Inflammatory Stimuli ◽  
Molecular Etiology ◽  
Socioeconomic Burden ◽  
Vascular Syndromes ◽  
Post Transcriptional Regulation

Cardiovascular disease remains a major medical and socioeconomic burden in developed and developing societies, and will increase with an aging and increasingly sedentary society. Vascular disease and atherosclerotic vascular syndromes are essentially inflammatory disorders, and transcriptional and post-transcriptional processes play essential roles in the ability of resident vascular and inflammatory cells to adapt to environmental stimuli. The regulation of mRNA translocation, stability, and translation are key processes of post-transcriptional regulation that permit these cells to rapidly respond to inflammatory stimuli. For the most part, these processes are controlled by elements in the 3′-UTR of labile, proinflammatory transcripts. Since proinflammatory transcripts almost exclusively contain AU-rich elements (AREs), this represents a tightly regulated and specific mechanism for initiation and maintenance of the proinflammatory phenotype. RNA-binding proteins (RBPs) recognize cis elements in 3′-UTR, and regulate each of these processes, but there is little literature exploring the concept that RBPs themselves can be directly regulated by inflammatory stimuli. Conceptually, inflammation-responsive RBPs represent an attractive target of rational therapies to combat vascular inflammatory syndromes. Herein we briefly describe the cellular and molecular etiology of atherosclerosis, and summarize our current understanding of RBPs and their specific roles in regulation of inflammatory mRNA stability. We also detail RBPs as targets of current anti-inflammatory modalities and how this may translate into better treatment for vascular inflammatory diseases.

scholarly journals Protein Binding to Cis-Motifs in mRNAs Coding Sequence Is Common and Regulates Transcript Stability and the Rate of Translation

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2910
Author(s):  
Ewa A. Grzybowska ◽  
Maciej Wakula
Keyword(s):  
Protein Binding ◽  
High Throughput ◽  
Mrna Stability ◽  
Regulatory Network ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Translational Efficiency ◽  
Coding Sequence ◽  
Transcript Stability ◽  
Coding Regions

Protein binding to the non-coding regions of mRNAs is relatively well characterized and its functionality has been described in many examples. New results obtained by high-throughput methods indicate that binding to the coding sequence (CDS) by RNA-binding proteins is also quite common, but the functions thereof are more obscure. As described in this review, CDS binding has a role in the regulation of mRNA stability, but it has also a more intriguing role in the regulation of translational efficiency. Global approaches, which suggest the significance of CDS binding along with specific examples of CDS-binding RBPs and their modes of action, are outlined here, pointing to the existence of a relatively less-known regulatory network controlling mRNA stability and translation on yet another level.

scholarly journals TREND-DB – A Transcriptome-wide Atlas of the Dynamic Landscape of Alternative Polyadenylation

2020 ◽  
Author(s):  
Federico Marini ◽  
Denise Scherzinger ◽  
Sven Danckwardt
Keyword(s):  
Gene Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Therapeutic Potential ◽  
Alternative Polyadenylation ◽  
Functional Enrichment ◽  
Rna Modifications ◽  
Posttranscriptional Gene Regulation ◽  
Individual Transcript ◽  
Dynamic Landscape

AbstractAlternative polyadenylation (APA) profoundly expands the transcriptome complexity. Perturbations of APA can disrupt biological processes, ultimately resulting in devastating disorders. A major challenge in identifying mechanisms and consequences of APA (and its perturbations) lies in the complexity of RNA 3’end processing, involving poorly conserved RNA motifs and multi-component complexes consisting of far more than 50 proteins. This is further complicated in that RNA 3’end maturation is closely linked to transcription, RNA processing, and even epigenetic (histone/DNA/RNA) modifications. Here we present TREND-DB (http://shiny.imbei.uni-mainz.de:3838/trend-db), a resource cataloging the dynamic landscape of APA after depletion of >170 proteins involved in various facets of transcriptional, co- and posttranscriptional gene regulation, epigenetic modifications, and further processes. TREND-DB visualizes the dynamics of transcriptome 3’end diversification (TREND) in a highly interactive manner; it provides a global APA network map and allows interrogating genes affected by specific APA-regulators, and vice versa. It also permits condition-specific functional enrichment analyses of APA-affected genes, which suggest wide biological and clinical relevance across all RNAi conditions. The implementation of the UCSC Genome Browser provides additional customizable layers of gene regulation accounting for individual transcript isoforms (e.g. epigenetics, miRNA binding sites, RNA-binding proteins). TREND-DB thereby fosters disentangling the role of APA for various biological programs, including potential disease mechanisms, and helps to identify their diagnostic and therapeutic potential.

scholarly journals TREND-DB—a transcriptome-wide atlas of the dynamic landscape of alternative polyadenylation

2020 ◽  
Vol 49 (D1) ◽  
pp. D243-D253
Author(s):  
Federico Marini ◽  
Denise Scherzinger ◽  
Sven Danckwardt
Keyword(s):  
Gene Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Therapeutic Potential ◽  
Alternative Polyadenylation ◽  
Functional Enrichment ◽  
Rna Modifications ◽  
Individual Transcript ◽  
Dynamic Landscape ◽  
Transcriptional Gene Regulation

Abstract Alternative polyadenylation (APA) profoundly expands the transcriptome complexity. Perturbations of APA can disrupt biological processes, ultimately resulting in devastating disorders. A major challenge in identifying mechanisms and consequences of APA (and its perturbations) lies in the complexity of RNA 3′ end processing, involving poorly conserved RNA motifs and multi-component complexes consisting of far more than 50 proteins. This is further complicated in that RNA 3′ end maturation is closely linked to transcription, RNA processing and even epigenetic (histone/DNA/RNA) modifications. Here, we present TREND-DB (http://shiny.imbei.uni-mainz.de:3838/trend-db), a resource cataloging the dynamic landscape of APA after depletion of >170 proteins involved in various facets of transcriptional, co- and post-transcriptional gene regulation, epigenetic modifications and further processes. TREND-DB visualizes the dynamics of transcriptome 3′ end diversification (TREND) in a highly interactive manner; it provides a global APA network map and allows interrogating genes affected by specific APA-regulators and vice versa. It also permits condition-specific functional enrichment analyses of APA-affected genes, which suggest wide biological and clinical relevance across all RNAi conditions. The implementation of the UCSC Genome Browser provides additional customizable layers of gene regulation accounting for individual transcript isoforms (e.g. epigenetics, miRNA-binding sites and RNA-binding proteins). TREND-DB thereby fosters disentangling the role of APA for various biological programs, including potential disease mechanisms, and helps identify their diagnostic and therapeutic potential.

scholarly journals Post-transcriptional regulation of inflammation by RNA-binding proteins via cis-elements of mRNAs

2019 ◽  
Vol 166 (5) ◽  
pp. 375-382 ◽  
Author(s):  
Yutaro Uchida ◽  
Tomoki Chiba ◽  
Ryota Kurimoto ◽  
Hiroshi Asahara
Keyword(s):  
Transcriptional Regulation ◽  
Lupus Erythematosus ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulatory Elements ◽  
Translational Efficiency ◽  
Rapid Induction ◽  
Post Transcriptional Regulation

Abstract In human genome, there are approximately 1,500 RNA-binding proteins (RBPs). They can regulate mRNA stability or translational efficiency via ribosomes and these processes are known as ‘post-transcriptional regulation’. Accumulating evidences indicate that post-transcriptional regulation is the determinant of the accurate levels of cytokines mRNAs. While transcriptional regulation of cytokines mRNAs has been well studied and found to be important for the rapid induction of mRNA and regulation of the acute phase of inflammation, post-transcriptional regulation by RBPs is essential for resolving inflammation in the later phase, and their dysfunction may lead to severe autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus. For post-transcriptional regulation, RBPs recognize and directly bind to cis-regulatory elements in 3′ untranslated region of mRNAs such as AU-rich or constitutive decay elements and play various roles. In this review, we summarize the recent findings regarding the role of RBPs in the regulation of inflammation.

scholarly journals Novel Insights into YB-1 Signaling and Cell Death Decisions

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3306
Author(s):  
Aneri Shah ◽  
Jonathan A. Lindquist ◽  
Lars Rosendahl ◽  
Ingo Schmitz ◽  
Peter R. Mertens
Keyword(s):  
Stress Responses ◽  
Rna Splicing ◽  
Cell Cycle Progression ◽  
Rna Binding ◽  
Inflammatory Responses ◽  
Rna Binding Proteins ◽  
Inflammatory Diseases ◽  
Therapeutic Option ◽  
Tumor Therapy ◽  
Inflammatory Microenvironment

YB-1 belongs to the evolutionarily conserved cold-shock domain protein family of RNA binding proteins. YB-1 is a well-known transcriptional and translational regulator, involved in cell cycle progression, DNA damage repair, RNA splicing, and stress responses. Cell stress occurs in many forms, e.g., radiation, hyperthermia, lipopolysaccharide (LPS) produced by bacteria, and interferons released in response to viral infection. Binding of the latter factors to their receptors induces kinase activation, which results in the phosphorylation of YB-1. These pathways also activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a well-known transcription factor. NF-κB is upregulated following cellular stress and orchestrates inflammatory responses, cell proliferation, and differentiation. Inflammation and cancer are known to share common mechanisms, such as the recruitment of infiltrating macrophages and development of an inflammatory microenvironment. Several recent papers elaborate the role of YB-1 in activating NF-κB and signaling cell survival. Depleting YB-1 may tip the balance from survival to enhanced apoptosis. Therefore, strategies that target YB-1 might be a viable therapeutic option to treat inflammatory diseases and improve tumor therapy.

scholarly journals RNA m6A modification orchestrates a LINE-1–host interaction that facilitates retrotransposition and contributes to long gene vulnerability

Cell Research ◽  
2021 ◽  
Author(s):  
Feng Xiong ◽  
Ruoyu Wang ◽  
Joo-Hyung Lee ◽  
Shenglan Li ◽  
Shin-Fu Chen ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulatory Elements ◽  
Host Interaction ◽  
Damage Repair ◽  
Novel Host ◽  
Cell Type Specific ◽  
Human Fetal Tissues ◽  
Long Genes

AbstractThe molecular basis underlying the interaction between retrotransposable elements (RTEs) and the human genome remains poorly understood. Here, we profiled N6-methyladenosine (m6A) deposition on nascent RNAs in human cells by developing a new method MINT-Seq, which revealed that many classes of RTE RNAs, particularly intronic LINE-1s (L1s), are strongly methylated. These m6A-marked intronic L1s (MILs) are evolutionarily young, sense-oriented to hosting genes, and are bound by a dozen RNA binding proteins (RBPs) that are putative novel readers of m6A-modified RNAs, including a nuclear matrix protein SAFB. Notably, m6A positively controls the expression of both autonomous L1s and co-transcribed L1 relics, promoting L1 retrotransposition. We showed that MILs preferentially reside in long genes with critical roles in DNA damage repair and sometimes in L1 suppression per se, where they act as transcriptional “roadblocks” to impede the hosting gene expression, revealing a novel host-weakening strategy by the L1s. In counteraction, the host uses the SAFB reader complex to bind m6A-L1s to reduce their levels, and to safeguard hosting gene transcription. Remarkably, our analysis identified thousands of MILs in multiple human fetal tissues, enlisting them as a novel category of cell-type-specific regulatory elements that often compromise transcription of long genes and confer their vulnerability in neurodevelopmental disorders. We propose that this m6A-orchestrated L1–host interaction plays widespread roles in gene regulation, genome integrity, human development and diseases.

scholarly journals Massively parallel identification of zipcodes in primary cortical neurons

2021 ◽  
Author(s):  
Nicolai von Kuegelgen ◽  
Samantha Mendonsa ◽  
Sayaka Dantsuji ◽  
Maya Ron ◽  
Marieluise Kirchner ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Rna Binding ◽  
De Novo ◽  
Rna Binding Proteins ◽  
Regulatory Elements ◽  
Massively Parallel ◽  
Primary Cortical Neurons ◽  
Subcellular Compartments ◽  
Local Functions ◽  
Massively Parallel Reporter Assay

Cells adopt highly polarized shapes and form distinct subcellular compartments largely due to the localization of many mRNAs to specific areas, where they are translated into proteins with local functions. This mRNA localization is mediated by specific cis-regulatory elements in mRNAs, commonly called "zipcodes." Their recognition by RNA-binding proteins (RBPs) leads to the integration of the mRNAs into macromolecular complexes and their localization. While there are hundreds of localized mRNAs, only a few zipcodes have been characterized. Here, we describe a novel neuronal zipcode identification protocol (N-zip) that can identify zipcodes across hundreds of 3'UTRs. This approach combines a method of separating the principal subcellular compartments of neurons - cell bodies and neurites - with a massively parallel reporter assay. Our analysis identifies the let-7 binding site and (AU)n motif as de novo zipcodes in mouse primary cortical neurons and suggests a strategy for detecting many more.

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