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 Post-Transcriptional Regulation of Immune Responses and Inflammatory Diseases by RNA-Binding ZFP36 Family Proteins

2021 ◽  
Vol 12 ◽  
Author(s):  
Sohei Makita ◽  
Hiroaki Takatori ◽  
Hiroshi Nakajima
Keyword(s):  
Transcriptional Regulation ◽  
Zinc Finger ◽  
Messenger Rna ◽  
Rna Binding ◽  
Cell Function ◽  
Zinc Finger Protein ◽  
Rna Binding Proteins ◽  
Inflammatory Diseases ◽  
Expression Patterns ◽  
Post Transcriptional Regulation

Post-transcriptional regulation is involved in the regulation of many inflammatory genes. Zinc finger protein 36 (ZFP36) family proteins are RNA-binding proteins involved in messenger RNA (mRNA) metabolism pathways. The ZFP36 family is composed of ZFP36 (also known as tristetraprolin, TTP), ZFP36L1, ZFP36L2, and ZFP36L3 (only in rodents). The ZFP36 family proteins contain two tandemly repeated CCCH-type zinc-finger motifs, bind to adenine uridine-rich elements in the 3’-untranslated regions (3’ UTR) of specific mRNA, and lead to target mRNA decay. Although the ZFP36 family members are structurally similar, they are known to play distinct functions and regulate different target mRNAs, probably due to their cell-type-specific expression patterns. For instance, ZFP36 has been well-known to function as an anti-inflammatory modulator in murine models of systemic inflammatory diseases by down-regulating the production of various pro-inflammatory cytokines, including TNF-α. Meanwhile, ZFP36L1 is required for the maintenance of the marginal-zone B cell compartment. Recently, we found that ZFP36L2 reduces the expression of Ikzf2 (encoding HELIOS) and suppresses regulatory T cell function. This review summarizes the current understanding of the post-transcriptional regulation of immunological responses and inflammatory diseases by RNA-binding ZFP36 family proteins.

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 C9orf72-associated arginine-rich dipeptide repeats induce RNA-dependent nuclear accumulation of Staufen in neurons

2021 ◽  
Author(s):  
Eun Seon Kim ◽  
Chang Geon Chung ◽  
Jeong Hyang Park ◽  
Byung Su Ko ◽  
Sung Soon Park ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Nuclear Accumulation ◽  
Heterozygous Mutation ◽  
Pathological Feature ◽  
Dependent Manner ◽  
Cellular Processes ◽  
Drosophila Model ◽  
Post Transcriptional Regulation

Abstract RNA-binding proteins (RBPs) play essential roles in diverse cellular processes through post-transcriptional regulation of RNAs. The subcellular localization of RBPs is thus under tight control, the breakdown of which is associated with aberrant cytoplasmic accumulation of nuclear RBPs such as TDP-43 and FUS, well-known pathological markers for amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). Here, we report in Drosophila model for ALS/FTD that nuclear accumulation of a cytoplasmic RBP, Staufen, may be a new pathological feature. We found that in Drosophila C4da neurons expressing PR36, one of the arginine-rich dipeptide repeat proteins (DPRs), Staufen accumulated in the nucleus in Importin- and RNA-dependent manner. Notably, expressing Staufen with exogenous NLS—but not with mutated endogenous NLS—potentiated PR-induced dendritic defect, suggesting that nuclear-accumulated Staufen can enhance PR toxicity. PR36 expression increased Fibrillarin staining in the nucleolus, which was enhanced by heterozygous mutation of stau (stau+/−), a gene that codes Staufen. Furthermore, knockdown of fib, which codes Fibrillarin, exacerbated retinal degeneration mediated by PR toxicity, suggesting that increased amount of Fibrillarin by stau+/− is protective. Stau+/− also reduced the amount of PR-induced nuclear-accumulated Staufen and mitigated retinal degeneration and rescued viability of flies expressing PR36. Taken together, our data show that nuclear accumulation of Staufen in neurons may be an important pathological feature contributing to the pathogenesis of ALS/FTD.

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 Mamo decodes hierarchical temporal gradients into terminal neuronal fate

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Ling-Yu Liu ◽  
Xi Long ◽  
Ching-Po Yang ◽  
Rosa L Miyares ◽  
Ken Sugino ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Neuronal Diversity ◽  
Temporal Expression ◽  
Identity Maintenance ◽  
Temporal Gene Expression ◽  
Neuronal Fate ◽  
Mammalian Genes ◽  
Post Transcriptional Regulation

Temporal patterning is a seminal method of expanding neuronal diversity. Here we unravel a mechanism decoding neural stem cell temporal gene expression and transforming it into discrete neuronal fates. This mechanism is characterized by hierarchical gene expression. First, Drosophila neuroblasts express opposing temporal gradients of RNA-binding proteins, Imp and Syp. These proteins promote or inhibit chinmo translation, yielding a descending neuronal gradient. Together, first and second-layer temporal factors define a temporal expression window of BTB-zinc finger nuclear protein, Mamo. The precise temporal induction of Mamo is achieved via both transcriptional and post-transcriptional regulation. Finally, Mamo is essential for the temporally defined, terminal identity of α’/β’ mushroom body neurons and identity maintenance. We describe a straightforward paradigm of temporal fate specification where diverse neuronal fates are defined via integrating multiple layers of gene regulation. The neurodevelopmental roles of orthologous/related mammalian genes suggest a fundamental conservation of this mechanism in brain development.

Post-transcriptional regulation in hematopoiesis: RNA binding proteins take control

2019 ◽  
Vol 97 (1) ◽  
pp. 10-20 ◽  
Author(s):  
Laura P.M.H. de Rooij ◽  
Derek C.H. Chan ◽  
Ava Keyvani Chahi ◽  
Kristin J. Hope
Keyword(s):  
Transcriptional Regulation ◽  
Stem Cell ◽  
Cell Fate ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Control Of Gene Expression ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Post Transcriptional Regulation

Normal hematopoiesis is sustained through a carefully orchestrated balance between hematopoietic stem cell (HSC) self-renewal and differentiation. The functional importance of this axis is underscored by the severity of disease phenotypes initiated by abnormal HSC function, including myelodysplastic syndromes and hematopoietic malignancies. Major advances in the understanding of transcriptional regulation of primitive hematopoietic cells have been achieved; however, the post-transcriptional regulatory layer that may impinge on their behavior remains underexplored by comparison. Key players at this level include RNA-binding proteins (RBPs), which execute precise and highly coordinated control of gene expression through modulation of RNA properties that include its splicing, polyadenylation, localization, degradation, or translation. With the recent identification of RBPs having essential roles in regulating proliferation and cell fate decisions in other systems, there has been an increasing appreciation of the importance of post-transcriptional control at the stem cell level. Here we discuss our current understanding of RBP-driven post-transcriptional regulation in HSCs, its implications for normal, perturbed, and malignant hematopoiesis, and the most recent technological innovations aimed at RBP–RNA network characterization at the systems level. Emerging evidence highlights RBP-driven control as an underappreciated feature of primitive hematopoiesis, the greater understanding of which has important clinical implications.

scholarly journals Aberrant Post-Transcriptional Regulation of Protein Expression in the Development of Chronic Obstructive Pulmonary Disease

2021 ◽  
Vol 22 (21) ◽  
pp. 11963
Author(s):  
Noof Aloufi ◽  
Aeshah Alluli ◽  
David H. Eidelman ◽  
Carolyn J. Baglole
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Transcriptional Regulation ◽  
Pulmonary Disease ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Chronic Obstructive ◽  
Respiratory Disorder ◽  
Obstructive Pulmonary Disease ◽  
Cellular Processes ◽  
Post Transcriptional Regulation

Chronic obstructive pulmonary disease (COPD) is an incurable and prevalent respiratory disorder that is characterized by chronic inflammation and emphysema. COPD is primarily caused by cigarette smoke (CS). CS alters numerous cellular processes, including the post-transcriptional regulation of mRNAs. The identification of RNA-binding proteins (RBPs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) as main factors engaged in the regulation of RNA biology opens the door to understanding their role in coordinating physiological cellular processes. Dysregulation of post-transcriptional regulation by foreign particles in CS may lead to the development of diseases such as COPD. Here we review current knowledge about post-transcriptional events that may be involved in the pathogenesis of COPD.

scholarly journals RNA-binding protein SORBS2 suppresses clear cell renal cell carcinoma metastasis by enhancing MTUS1 mRNA stability

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Qi Lv ◽  
Fan Dong ◽  
Yong Zhou ◽  
Zhiping Cai ◽  
Gangmin Wang
Keyword(s):  
Tumor Suppressor ◽  
Mrna Stability ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cell Renal Cell Carcinoma ◽  
Renal Cell Carcinoma Metastasis ◽  
Metastatic Capacity ◽  
Cancer Types ◽  
Carcinoma Metastasis ◽  
Ccrcc Cell

AbstractRNA-binding proteins (RBPs) predominantly contribute to abnormal posttranscriptional gene modulation and disease progression in cancer. Sorbin and SH3 domain-containing 2 (SORBS2), an RBP, has been reported to be a potent tumor suppressor in several cancer types. Through integrative analysis of clinical specimens, we disclosed that the expression level of SORBS2 was saliently decreased in metastatic tissues and positively correlated with overall survival. We observed that overexpression of SORBS2 brought about decreased metastatic capacity in ccRCC cell lines. Transcriptome-wide analysis revealed that SORBS2 notably increased microtubule-associated tumor-suppressor 1 gene (MTUS1) expression. In-depth mechanistic exploring discovered that the Cys2-His2 zinc finger (C2H2-ZnF) domain of SORBS2 directly bound to the 3′ untranslated region (3′UTR) of MTUS1 mRNA, which increased MTUS1 mRNA stability. In addition, we identified that MTUS1 regulated microtubule dynamics via promoting KIF2CS192 phosphorylation by Aurora B. Together, our research identified SORBS2 as a suppressor of ccRCC metastasis by enhancing MTUS1 mRNA stability, providing a novel understanding of RBPs during ccRCC progression.

scholarly journals Control of Cytokine mRNA Expression by RNA-binding Proteins and microRNAs

2012 ◽  
Vol 91 (7) ◽  
pp. 651-658 ◽  
Author(s):  
V. Palanisamy ◽  
A. Jakymiw ◽  
E.A. Van Tubergen ◽  
N.J. D’Silva ◽  
K.L. Kirkwood
Keyword(s):  
Cancer Progression ◽  
Mrna Stability ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Periodontal Diseases ◽  
Pharyngeal Cancer ◽  
Cytokine Mrna ◽  
Mediators Of Inflammation ◽  
The Stability

Cytokines are critical mediators of inflammation and host defenses. Regulation of cytokines can occur at various stages of gene expression, including transcription, mRNA export, and post- transcriptional and translational levels. Among these modes of regulation, post-transcriptional regulation has been shown to play a vital role in controlling the expression of cytokines by modulating mRNA stability. The stability of cytokine mRNAs, including TNFα, IL-6, and IL-8, has been reported to be altered by the presence of AU-rich elements (AREs) located in the 3′-untranslated regions (3′UTRs) of the mRNAs. Numerous RNA-binding proteins and microRNAs bind to these 3′UTRs to regulate the stability and/or translation of the mRNAs. Thus, this paper describes the cooperative function between RNA-binding proteins and miRNAs and how they regulate AU-rich elements containing cytokine mRNA stability/degradation and translation. These mRNA control mechanisms can potentially influence inflammation as it relates to oral biology, including periodontal diseases and oral pharyngeal cancer progression.

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