scholarly journals Extracellular mRNA transported to the nucleus exerts translation-independent function

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Takeshi Tomita ◽  
Masayoshi Kato ◽  
Taishi Mishima ◽  
Yuta Matsunaga ◽  
Hideki Sanjo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Membrane ◽  
Cell Nucleus ◽  
Untranslated Region ◽  
Rna Binding ◽  
Nk Cell ◽  
Interferon Γ ◽  
Independent Function ◽  
Cellular Functions ◽  
Migration Activity

AbstractRNA in extracellular vesicles (EVs) are uptaken by cells, where they regulate fundamental cellular functions. EV-derived mRNA in recipient cells can be translated. However, it is still elusive whether “naked nonvesicular extracellular mRNA” (nex-mRNA) that are not packed in EVs can be uptaken by cells and, if so, whether they have any functions in recipient cells. Here, we show the entrance of nex-mRNA in the nucleus, where they exert a translation-independent function. Human nex-interleukin-1β (IL1β)-mRNA outside cells proved to be captured by RNA-binding zinc finger CCCH domain containing protein 12D (ZC3H12D)-expressing human natural killer (NK) cells. ZC3H12D recruited to the cell membrane binds to the 3′-untranslated region of nex-IL1β-mRNA and transports it to the nucleus. The nex-IL1β-mRNA in the NK cell nucleus upregulates antiapoptotic gene expression, migration activity, and interferon-γ production, leading to the killing of cancer cells and antimetastasis in mice. These results implicate the diverse actions of mRNA.

scholarly journals Sonoporation: Underlying Mechanisms and Applications in Cellular Regulation

2021 ◽  
Author(s):  
Yue Li ◽  
Zhiyi Chen ◽  
Shuping Ge
Keyword(s):  
Gene Expression ◽  
Cell Membrane ◽  
State Of The Art ◽  
Cellular Functions ◽  
Cellular Regulation ◽  
Current State ◽  
Cellular Apoptosis ◽  
Ultrasonic Parameters ◽  
Or Gene ◽  
Underlying Mechanisms

Ultrasound combined with microbubble-mediated sonoporation has been applied to enhance drug or gene intracellular delivery. Sonoporation leads to the formation of openings in the cell membrane, triggered by ultrasound-mediated oscillations and destruction of microbubbles. Multiple mechanisms are involved in the occurrence of sonoporation, including ultrasonic parameters, microbubbles size, and the distance of microbubbles to cells. Recent advances are beginning to extend applications through the assistance of contrast agents, which allow ultrasound to connect directly to cellular functions such as gene expression, cellular apoptosis, differentiation, and even epigenetic reprogramming. In this review, we summarize the current state of the art concerning microbubble–cell interactions and sonoporation effects leading to cellular functions.

Combined Microscopy and Hyperelastic Warping for the Measurement of Intranuclear Mechanics in Native 3D Tissue

2013 ◽  
Author(s):  
Jonathan T. Henderson ◽  
Garrett Shannon ◽  
Alexander I. Veress ◽  
Corey P. Neu
Keyword(s):  
Gene Expression ◽  
Cell Nucleus ◽  
Environmental Changes ◽  
Important Determinant ◽  
Mechanical Forces ◽  
Cellular Functions ◽  
Native Tissue ◽  
Combined Microscopy ◽  
In Cells

The cell nucleus directs the regulation of normal cellular functions as well as the expression of proteins required for adaption to environmental changes. Mechanical forces are an important determinant of gene expression, and yet the measurement of intranuclear mechanics (e.g. strain) in cells embedded within their native tissue in situ remains a challenge.

scholarly journals New Insights into the Interplay between Non-Coding RNAs and RNA-Binding Protein HnRNPK in Regulating Cellular Functions

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 62 ◽  
Author(s):  
Yongjie Xu ◽  
Wei Wu ◽  
Qiu Han ◽  
Yaling Wang ◽  
Cencen Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mammalian Cells ◽  
Rna Binding ◽  
Binding Protein ◽  
Genomic Structure ◽  
Rna Binding Protein ◽  
Stem Cell Differentiation ◽  
Cellular Functions ◽  
Non Coding Rnas ◽  
Conserved Gene

The emerging data indicates that non-coding RNAs (ncRNAs) epresent more than the “junk sequences” of the genome. Both miRNAs and long non-coding RNAs (lncRNAs) are involved in fundamental biological processes, and their deregulation may lead to oncogenesis and other diseases. As an important RNA-binding protein (RBP), heterogeneous nuclear ribonucleoprotein K (hnRNPK) is known to regulate gene expression through the RNA-binding domain involved in various pathways, such as transcription, splicing, and translation. HnRNPK is a highly conserved gene that is abundantly expressed in mammalian cells. The interaction of hnRNPK and ncRNAs defines the novel way through which ncRNAs affect the expression of protein-coding genes and form autoregulatory feedback loops. This review summarizes the interactions of hnRNPK and ncRNAs in regulating gene expression at transcriptional and post-transcriptional levels or by changing the genomic structure, highlighting their involvement in carcinogenesis, glucose metabolism, stem cell differentiation, virus infection and other cellular functions. Drawing connections between such discoveries might provide novel targets to control the biological outputs of cells in response to different stimuli.

scholarly journals JNK activation decreases PP2A regulatory subunit B56α expression and mRNA stability and increases AUF1 expression in cardiomyocytes

2006 ◽  
Vol 291 (3) ◽  
pp. H1183-H1192 ◽  
Author(s):  
Nicole D. Glaser ◽  
Yevgeniya O. Lukyanenko ◽  
Yibin Wang ◽  
Gerald M. Wilson ◽  
Terry B. Rogers
Keyword(s):  
Gene Expression ◽  
Untranslated Region ◽  
Time Course ◽  
Rna Binding ◽  
Cardiac Cells ◽  
Regulatory Subunit ◽  
Central Feature ◽  
Mobility Shift ◽  
Gel Mobility Shift ◽  
Jnk Activation

A central feature of heart disease is a molecular remodeling of signaling pathways in cardiac myocytes. This study focused on novel molecular elements of MAPK-mediated alterations in the pattern of gene expression of the protein phosphatase 2A (PP2A). In an established model of sustained JNK activation, a 70% decrease in expression of the targeting subunit of PP2A, B56α, was observed in either neonatal or adult cardiomyocytes. This loss in protein abundance was accompanied by a decrease of 69% in B56α mRNA steady-state levels. Given that the 3′-untranslated region of this transcript contains adenylate-uridylate-rich elements known to regulate mRNA degradation, experiments explored the notion that instability of B56α mRNA accounts for the response. mRNA time-course analyses with real-time PCR methods showed that B56α transcript was transformed from a stable (no significant decay over 1 h) to a labile form that rapidly degraded within minutes. These results were supported by complementary experiments that revealed that the RNA-binding protein AUF1, known to destabilize target mRNA, was increased fourfold in JNK-activated cells. A variety of other stress-related stimuli, such as p38 MAPK activation and phorbol ester, upregulated AUF1 expression in cultured cardiac cells as well. In addition, gel mobility shift assays demonstrated that p37AUF1 binds with nanomolar affinity to segments of the B56α 3′-untranslated region. Thus these studies provide new evidence that signaling-induced mRNA instability is an important mechanism that underlies the changes in the pattern of gene expression evoked by stress-activated pathways in cardiac cells.

scholarly journals Several different sequences are implicated in bloodstream-form-specific gene expression in Trypanosoma brucei

2021 ◽  
Author(s):  
Tania Bishola Tshitenge ◽  
Lena Reichert ◽  
Bin Liu ◽  
Christine Clayton
Keyword(s):  
Gene Expression ◽  
Trypanosoma Brucei ◽  
Untranslated Region ◽  
Rna Binding ◽  
Binding Protein ◽  
Developmental Regulation ◽  
Rna Binding Protein ◽  
Bloodstream Form ◽  
Tsetse Flies ◽  
Specific Gene

The parasite Trypanosoma brucei grows as bloodstream forms in mammalian hosts, and as procyclic forms in tsetse flies. In trypanosomes, gene expression regulation depends heavily on post-transcriptional mechanisms. Both the RNA-binding protein RBP10 and glycosomal phosphoglycerate kinase PGKC are expressed only in mammalian-infective forms. RBP10 targets procyclic-specific mRNAs for destruction, while PGKC is required for bloodstream-form glycolysis. Developmental regulation of both is essential: expression of either RBP10 or PGKC in procyclic forms inhibits their proliferation. We show that the 3′-untranslated region of the RBP10 mRNA is extraordinarily long - 7.3kb - and were able to identify six different sequences, scattered across the untranslated region, which can independently cause bloodstream-form-specific expression. The 3′-untranslated region of the PGKC mRNA, although much shorter, still contains two different regions, of 125 and 153nt, that independently gave developmental regulation. No short consensus sequences were identified that were enriched either within these regulatory regions, or when compared with other mRNAs with similar regulation, suggesting that more than one regulatory RNA-binding protein is important for repression of mRNAs in procyclic forms. We also identified regions, including an AT repeat, that increased expression in bloodstream forms, or suppressed it in both forms. Trypanosome mRNAs that encode RNA-binding proteins often have extremely extended 3′-untranslated regions. We suggest that one function of this might be to act as a fail-safe mechanism to ensure correct regulation even if mRNA processing or expression of trans regulators is defective.

scholarly journals The PP2A inhibitor SET regulates natural killer cell IFN-γ production

2007 ◽  
Vol 204 (10) ◽  
pp. 2397-2405 ◽  
Author(s):  
Rossana Trotta ◽  
David Ciarlariello ◽  
Jessica Dal Col ◽  
Jeffrey Allard ◽  
Paolo Neviani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Immune Surveillance ◽  
Critical Factor ◽  
Interferon Γ ◽  
Pp2a Activity ◽  
Ifn Γ

Monokines (i.e., interleukin [IL]-12, -18, and -15) induce natural killer (NK) cells to produce interferon-γ (IFN-γ), which is a critical factor for immune surveillance of cancer and monocyte clearance of infection. We show that SET, which is a potent inhibitor of protein phosphatase type 2A (PP2A) activity, is highly expressed in human CD56bright NK cells, which produce more IFN-γ than CD56dim NK cells. SET was up-regulated upon monokine stimulation of primary human NK cells. Furthermore, ectopic overexpression of SET significantly enhanced IFN-γ gene expression in monokine-stimulated NK cells. In contrast, RNAi-mediated suppression of SET expression renders NK cells inefficient in producing high levels of IFN-γ in response to monokine costimulation. Mechanistically, suppression of PP2A activity by SET is important for IFN-γ gene expression in NK cells. In fact, treatment of primary human NK cells with the PP2A activator 1,9-dideoxy-forskolin, as well as administration of the drug to C57BL/6 mice, significantly reduced NK-dependent IFN-γ production in response to monokine treatment. Further, SET knockdown or pharmacologic activation of PP2A diminished extracellular signal-regulated kinase 1/2, p65RelA, signal transducer and activator of transduction 4 (STAT4), and STAT5 activity in monokine-stimulated NK cells, potentially contributing to the reduction in IFN-γ gene expression. Thus, SET expression is essential for suppressing PP2A phosphatase activity that would otherwise limit NK cell antitumoral and/or antiinflammatory functions by impairing NK cell production of IFN-γ.

The Therapeutic Potential and Role of miRNA, lncRNA, and circRNA in Osteoarthritis

2019 ◽  
Vol 19 (4) ◽  
pp. 255-263 ◽  
Author(s):  
Yuangang Wu ◽  
Xiaoxi Lu ◽  
Bin Shen ◽  
Yi Zeng
Keyword(s):  
Gene Expression ◽  
Gene Therapy ◽  
Extracellular Matrix ◽  
Inflammatory Reaction ◽  
Noncoding Rna ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Protein Translation ◽  
Cochrane Library

Background: Osteoarthritis (OA) is a disease characterized by progressive degeneration, joint hyperplasia, narrowing of joint spaces, and extracellular matrix metabolism. Recent studies have shown that the pathogenesis of OA may be related to non-coding RNA, and its pathological mechanism may be an effective way to reduce OA. Objective: The purpose of this review was to investigate the recent progress of miRNA, long noncoding RNA (lncRNA) and circular RNA (circRNA) in gene therapy of OA, discussing the effects of this RNA on gene expression, inflammatory reaction, apoptosis and extracellular matrix in OA. Methods: The following electronic databases were searched, including PubMed, EMBASE, Web of Science, and the Cochrane Library, for published studies involving the miRNA, lncRNA, and circRNA in OA. The outcomes included the gene expression, inflammatory reaction, apoptosis, and extracellular matrix. Results and Discussion: With the development of technology, miRNA, lncRNA, and circRNA have been found in many diseases. More importantly, recent studies have found that RNA interacts with RNA-binding proteins to regulate gene transcription and protein translation, and is involved in various pathological processes of OA, thus becoming a potential therapy for OA. Conclusion: In this paper, we briefly introduced the role of miRNA, lncRNA, and circRNA in the occurrence and development of OA and as a new target for gene therapy.

scholarly journals STAU2 protein level is controlled by caspases and the CHK1 pathway and regulates cell cycle progression in the non-transformed hTERT-RPE1 cells

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Lionel Condé ◽  
Yulemi Gonzalez Quesada ◽  
Florence Bonnet-Magnaval ◽  
Rémy Beaujois ◽  
Luc DesGroseillers
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Dna Damage ◽  
Steady State ◽  
Posttranscriptional Regulation ◽  
Cell Cycle Progression ◽  
Rna Binding ◽  
Regulation Of Gene Expression ◽  
Cycle Progression

AbstractBackgroundStaufen2 (STAU2) is an RNA binding protein involved in the posttranscriptional regulation of gene expression. In neurons, STAU2 is required to maintain the balance between differentiation and proliferation of neural stem cells through asymmetric cell division. However, the importance of controlling STAU2 expression for cell cycle progression is not clear in non-neuronal dividing cells. We recently showed that STAU2 transcription is inhibited in response to DNA-damage due to E2F1 displacement from theSTAU2gene promoter. We now study the regulation of STAU2 steady-state levels in unstressed cells and its consequence for cell proliferation.ResultsCRISPR/Cas9-mediated and RNAi-dependent STAU2 depletion in the non-transformed hTERT-RPE1 cells both facilitate cell proliferation suggesting that STAU2 expression influences pathway(s) linked to cell cycle controls. Such effects are not observed in the CRISPR STAU2-KO cancer HCT116 cells nor in the STAU2-RNAi-depleted HeLa cells. Interestingly, a physiological decrease in the steady-state level of STAU2 is controlled by caspases. This effect of peptidases is counterbalanced by the activity of the CHK1 pathway suggesting that STAU2 partial degradation/stabilization fines tune cell cycle progression in unstressed cells. A large-scale proteomic analysis using STAU2/biotinylase fusion protein identifies known STAU2 interactors involved in RNA translation, localization, splicing, or decay confirming the role of STAU2 in the posttranscriptional regulation of gene expression. In addition, several proteins found in the nucleolus, including proteins of the ribosome biogenesis pathway and of the DNA damage response, are found in close proximity to STAU2. Strikingly, many of these proteins are linked to the kinase CHK1 pathway, reinforcing the link between STAU2 functions and the CHK1 pathway. Indeed, inhibition of the CHK1 pathway for 4 h dissociates STAU2 from proteins involved in translation and RNA metabolism.ConclusionsThese results indicate that STAU2 is involved in pathway(s) that control(s) cell proliferation, likely via mechanisms of posttranscriptional regulation, ribonucleoprotein complex assembly, genome integrity and/or checkpoint controls. The mechanism by which STAU2 regulates cell growth likely involves caspases and the kinase CHK1 pathway.

Sign in / Sign up

Export Citation Format

Share Document