scholarly journals CCR4-NOT Deadenylates mRNA Associated with RNA-Induced Silencing Complexes in Human Cells

2010 ◽  
Vol 30 (6) ◽  
pp. 1486-1494 ◽  
Author(s):  
Xianghua Piao ◽  
Xue Zhang ◽  
Ligang Wu ◽  
Joel G. Belasco
Keyword(s):  
Small Rna ◽  
Small Interfering Rna ◽  
Inhibitory Effect ◽  
Human Cells ◽  
Predominant Role ◽  
Catalytic Subunits ◽  
Present Evidence ◽  
Mrna Targets ◽  
Protein Components ◽  
Interfering Rna

ABSTRACT MicroRNAs (miRNAs) repress gene expression posttranscriptionally by inhibiting translation and by expediting deadenylation so as to trigger rapid mRNA decay. Their regulatory influence is mediated by the protein components of the RNA-induced silencing complex (RISC), which deliver miRNAs and siRNAs to their mRNA targets. Here, we present evidence that CCR4-NOT is the deadenylase that removes poly(A) from messages destabilized by miRNAs in human cells. Overproducing a mutationally inactivated form of either of the catalytic subunits of this deadenylase (CCR4 or CAF1/POP2) significantly impedes the deadenylation and decay of mRNA targeted by a partially complementary miRNA. The same deadenylase initiates the degradation of “off-target” mRNAs that are bound by an imperfectly complementary siRNA introduced by transfection. The greater inhibitory effect of inactive CAF1 or POP2 (versus inactive CCR4) suggests a predominant role for this catalytic subunit of CCR4-NOT in miRNA- or small interfering RNA (siRNA)-mediated deadenylation. These effects of mi/siRNAs and CCR4-NOT can be fully reproduced by directly tethering RISC to mRNA without the guidance of a small RNA, indicating that the ability of RISC to accelerate deadenylation is independent of RNA base pairing. Despite its importance for mi/siRNA-mediated deadenylation, CCR4-NOT appears not to associate significantly with RISC, as judged by the failure of CAF1 and POP2 to coimmunoprecipitate detectably with either the Ago or TNRC6 subunit of RISC, a finding at odds with deadenylase recruitment as the mechanism by which RISC accelerates poly(A) removal.

scholarly journals The FDA-Approved Anti-Asthma Medicine Ciclesonide Inhibits Lung Cancer Stem Cells through Hedgehog Signaling-Mediated SOX2 Regulation

2020 ◽  
Vol 21 (3) ◽  
pp. 1014 ◽  
Author(s):  
Hack Sun Choi ◽  
Su-Lim Kim ◽  
Ji-Hyang Kim ◽  
Dong-Sun Lee
Keyword(s):  
Lung Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Small Interfering Rna ◽  
Hedgehog Signaling ◽  
Underlying Mechanism ◽  
Inhibitory Effect ◽  
Protein Levels ◽  
Lung Cancer Stem Cells ◽  
Interfering Rna

Ciclesonide is an FDA-approved glucocorticoid (GC) used to treat asthma and allergic rhinitis. However, its effects on cancer and cancer stem cells (CSCs) are unknown. Our study focuses on investigating the inhibitory effect of ciclesonide on lung cancer and CSCs and its underlying mechanism. In this study, we showed that ciclesonide inhibits the proliferation of lung cancer cells and the growth of CSCs. Similar glucocorticoids, such as dexamethasone and prednisone, do not inhibit CSC formation. We show that ciclesonide is important for CSC formation through the Hedgehog signaling pathway. Ciclesonide reduces the protein levels of GL1, GL2, and Smoothened (SMO), and a small interfering RNA (siRNA) targeting SMO inhibits tumorsphere formation. Additionally, ciclesonide reduces the transcript and protein levels of SOX2, and an siRNA targeting SOX2 inhibits tumorsphere formation. To regulate breast CSC formation, ciclesonide regulates GL1, GL2, SMO, and SOX2. Our results unveil a novel mechanism involving Hedgehog signaling and SOX2 regulated by ciclesonide in lung CSCs, and also open up the possibility of targeting Hedgehog signaling and SOX2 to prevent lung CSC formation.

scholarly journals Inhibitory effect of small interfering RNA on dengue virus replication in mosquito cells

2010 ◽  
Vol 7 (1) ◽  
pp. 270 ◽  
Author(s):  
Xinwei Wu ◽  
Hua Hong ◽  
Jinya Yue ◽  
Yejian Wu ◽  
Xiangzhong Li ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Virus Replication ◽  
Small Interfering Rna ◽  
Inhibitory Effect ◽  
Mosquito Cells ◽  
Interfering Rna

scholarly journals NBS1 Knockdown by Small Interfering RNA Increases Ionizing Radiation Mutagenesis and Telomere Association in Human Cells

2005 ◽  
Vol 65 (13) ◽  
pp. 5544-5553 ◽  
Author(s):  
Ying Zhang ◽  
Chang U.K. Lim ◽  
Eli S. Williams ◽  
Junqing Zhou ◽  
Qinming Zhang ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Small Interfering Rna ◽  
Human Cells ◽  
Telomere Association ◽  
Interfering Rna

Flt3 Mutations in Proximity to an Ubiquitin Dependent Endocytosis Motif Suspend Its Hdm2 Modulation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4320-4320
Author(s):  
Line Wergeland ◽  
Eystein Oveland ◽  
Gry Sjoholt ◽  
Siv Lise Bedringaas ◽  
Randi T. Hovland ◽  
...  
Keyword(s):  
Small Interfering Rna ◽  
Inhibitory Effect ◽  
Down Regulation ◽  
Reciprocal Regulation ◽  
Surface Receptors ◽  
Flt3 Mutations ◽  
Elevated Expression ◽  
Interfering Rna ◽  
Small Molecular Inhibitors ◽  
Tandem Duplications

Abstract Acute myeloid leukemia (AML) frequently features mutations in the receptor tyrosine kinase Flt3 and elevated expression of the oncogenic E3 ubiquitin ligase Hdm2. Additional to the p53 inhibitory effect of Hdm2, Hdm2 appears involved in endocytosis of cell surface receptors. In this study we explore the possibility of Flt3 modulation by Hdm2 in primary AML cells and cell lines (NB4 and MV4–11) with wild type Flt3 (Flt3-wt) or mutated Flt3 (Flt3-ITD). Flt3 ligand (FL), small molecular inhibitors and small interfering RNA (siRNA) were used to elucidate the relation between Flt3 and Hdm2 on protein level, mRNA expression and modulation of apoptosis. The basal level of Flt3 is higher in AML patients with Flt3-ITD than in patients with Flt3-wt. Flt3-ITD affects a ubiquitin endocytosis motif that in some patients are duplicated, possibly resulting in enhanced receptor cycling. Down-regulation of Flt3-wt by FL, small interfering RNA or PKC412 resulted in elevated level of Hdm2. Similarly, Hdm2 attenuation resulted in increased Flt3 protein expression. Flt3-ITD responded less to Flt3 down-regulation, and was only weakly responding to Hdm2 modulation. We demonstrate that modulation of Flt3 or Hdm2 results in reciprocal regulation, and that Flt3 with internal tandem duplications may suspend its Hdm2 modulation. Together, Flt3-ITD results in dysregulated receptor turnover and elevated Hdm2 thus interconnecting the two pathways of Flt3 and p53, both related to chemoresistance in AML.

scholarly journals Molecular mechanisms of Dicer: endonuclease and enzymatic activity

2017 ◽  
Vol 474 (10) ◽  
pp. 1603-1618 ◽  
Author(s):  
Min-Sun Song ◽  
John J. Rossi
Keyword(s):  
Enzymatic Activity ◽  
Small Rna ◽  
Small Rnas ◽  
Small Interfering Rna ◽  
Molecular Mechanisms ◽  
Cellular Processes ◽  
Interfering Rna ◽  
Exogenous Substrates

The enzyme Dicer is best known for its role as a riboendonuclease in the small RNA pathway. In this canonical role, Dicer is a critical regulator of the biogenesis of microRNA and small interfering RNA, as well as a growing number of additional small RNAs derived from various sources. Emerging evidence demonstrates that Dicer's endonuclease role extends beyond the generation of small RNAs; it is also involved in processing additional endogenous and exogenous substrates, and is becoming increasingly implicated in regulating a variety of other cellular processes, outside of its endonuclease function. This review will describe the canonical and newly identified functions of Dicer.

Effective expression of small interfering RNA in human cells

2002 ◽  
Vol 20 (5) ◽  
pp. 505-508 ◽  
Author(s):  
Cynthia P. Paul ◽  
Paul D. Good ◽  
Ira Winer ◽  
David R. Engelke
Keyword(s):  
Small Interfering Rna ◽  
Human Cells ◽  
Interfering Rna

scholarly journals Salient Genetic Notes on Small-RNAs and their Applications in Agricultural Biotechnology

2020 ◽  
pp. 1-17
Author(s):  
Samuel Amiteye
Keyword(s):  
Gene Regulation ◽  
Small Rna ◽  
Small Rnas ◽  
Small Interfering Rna ◽  
Crop Improvement ◽  
Regulation Of Gene Expression ◽  
Healthy Plant ◽  
Biological Processes ◽  
Protein Coding ◽  
Interfering Rna

Small-RNAs are 20 to 27 nucleotides long non-protein-coding RNAs that act on either DNA or RNA to effect the regulation of gene expression. Small-RNAs are key in genetic and epigenetic regulation of diverse biological processes and pathways in response to biotic and abiotic environmental stresses. The gene regulatory functions of small-RNA molecules enhance healthy plant growth and normal development by controlling biological processes such as flowering programming, fruit development, disease and pests resistance. Small-RNAs comprise mainly microRNA and small interfering RNA species. MicroRNAs have been proven to primarily engage in posttranscriptional gene regulation while small interfering RNA have been implicated mainly in transcriptional gene regulation. This review covers the recent advancements in small-RNA research in plants, with emphasis on particularly microRNAs and small interfering RNA biogenesis, biological functions and their relevance in the regulation of traits of agronomic importance in plants. Also discussed extensively is the potential biotechnological applications of these small-RNAs for crop improvement.

scholarly journals Inhibitory effect of survivin-targeting small interfering RNA on gastric cancer cells

2014 ◽  
Vol 13 (3) ◽  
pp. 6786-6803 ◽  
Author(s):  
Y.H. Li ◽  
M. Chen ◽  
M. Zhang ◽  
X.Q. Zhang ◽  
S. Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Small Interfering Rna ◽  
Inhibitory Effect ◽  
Gastric Cancer Cells ◽  
Interfering Rna

scholarly journals Silencing of AURKA augments the antitumor efficacy of the AURKA inhibitor MLN8237 on neuroblastoma cells

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Yan Yang ◽  
Lili Ding ◽  
Qi Zhou ◽  
Li Fen ◽  
Yuhua Cao ◽  
...  
Keyword(s):  
Small Interfering Rna ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Inhibitory Effect ◽  
Neuroblastoma Cell Line ◽  
Inhibitory Effects ◽  
Rna Transfection ◽  
Interfering Rna

Abstract Background Aurora kinase A (AURKA) has been implicated in the regulation of cell cycle progression, mitosis and a key number of oncogenic signaling pathways in various malignancies including neuroblastoma. Small molecule inhibitors of AURKA have shown potential, but still not as good as expected effects in clinical trials. Little is known about this underlying mechanism. Here, we evaluated the inhibitory effects of AURKA inhibitor MLN8237 on neuroblastoma cells to understand the potential mechanisms responsible for tumor therapy. Methods MLN8237 treatment on neuroblastoma cell line IMR32 was done and in vivo inhibitory effects were investigated using tumor xenograft model. Cellular senescence was evaluated by senescence-associated β-gal Staining assay. Flow cytometry was used to tested cell cycle arrest and cell apoptosis. Senescence-associated signal pathways were detected by western blot. CD133 microbeads and microsphere formation were used to separate and enrich CD133+ cells. AURKA small interfering RNA transfection was carried to downregulate AURKA level. Finally, the combination of MLN8237 treatment with AURKA small interfering RNA transfection were adopted to evaluate the inhibitory effect on neuroblastoma cells. Results We demonstrate that MLN8237, an inhibitor of AURKA, induces the neuroblastoma cell line IMR32 into cellular senescence and G2/M cell phase arrest. Inactivation of AURKA results in MYCN destabilization and inhibits cell growth in vitro and in a mouse model. Although MLN8237 inhibits AURKA kinase activity, it has almost no inhibitory effect on the AURKA protein level. By contrast, MLN8237 treatment leads to abnormal high expression of AURKA in vitro and in vivo. Knockdown of AURKA reduces cell survival. The combination of MLN8237 with AURKA small interfering RNA results in more profound inhibitory effects on neuroblastoma cell growth. Moreover, MLN8237 treatment followed by AURKA siRNA forces senescent cells into apoptosis via suppression of the Akt/Stat3 pathway. Conclusions The effect of AURKA-targeted inhibition of tumor growth plays roles in both the inactivation of AURKA activity and the decrease in the AURKA protein expression level.

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