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Ann Arbor, MI, United States

Deng J.,University of Texas Medical Branch | Deng J.,Zhejiang University | Ptashkin R.N.,miRcore | Ptashkin R.N.,University of Michigan | And 8 more authors.
Molecular Therapy - Nucleic Acids | Year: 2014

Small noncoding RNAs (sncRNAs), such as microRNAs (miRNA), virus-derived sncRNAs, and more recently identified tRNA-derived RNA fragments, are critical to posttranscriptional control of genes. Upon viral infection, host cells alter their sncRNA expression as a defense mechanism, while viruses can circumvent host defenses and promote their own propagation by affecting host cellular sncRNA expression or by expressing viral sncRNAs. Therefore, characterizing sncRNA profiles in response to viral infection is an important tool for understanding host-virus interaction, and for antiviral strategy development. Human metapneumovirus (hMPV), a recently identified pathogen, is a major cause of lower respiratory tract infections in infants and children. To investigate whether sncRNAs play a role in hMPV infection, we analyzed the changes in sncRNA profiles of airway epithelial cells in response to hMPV infection using ultrahigh-throughput sequencing. Of the cloned sncRNAs, miRNA was dominant in A549 cells, with the percentage of miRNA increasing in a time-dependent manner after the infection. In addition, several hMPV-derived sncRNAs and corresponding ribonucleases for their biogenesis were identified. hMPV M2-2 protein was revealed to be a key viral protein regulating miRNA expression. In summary, this study revealed several novel aspects of hMPV-mediated sncRNA expression, providing a new perspective on hMPV-host interactions. © 2014 The American Society of Gene & Cell Therapy. Source


Deng J.,University of Texas Medical Branch | Deng J.,Zhejiang University | Ptashkin R.N.,miRcore | Ptashkin R.N.,University of Michigan | And 10 more authors.
Molecular Therapy | Year: 2015

Target identification is highly instructive in defining the biological roles of microRNAs. However, little is known about other small noncoding RNAs; for example, tRNA-derived RNA Fragments (tRFs). Some tRFs exhibit a gene-silencing mechanism distinctly different from that of typical microRNAs. We recently demonstrated that a respiratory syncytial virus (RSV)-induced tRF, called tRF5-GluCTC, promotes RSV replication. RSV is the single most important cause of lower respiratory tract infection in children. By using biochemical screening and bioinformatics analyses, we have identified apolipoprotein E receptor 2 (APOER2) as a target of tRF5-GluCTC. The 3′-portion of tRF5-GluCTC recognizes a target site in the 3′-untranslated region of APOER2 and suppresses its expression. We have also discovered that APOER2 is an anti-RSV protein whose suppression by tRF5-GluCTC promotes RSV replication. Our report represents the first identification of a natural target of a tRF and illustrates how a virus utilizes a host tRF to control a host gene to favor its replication. Source


Shi X.,Donghua University | Lee I.,miRcore | Chen X.,University of Michigan | Zhu M.,Donghua University | And 2 more authors.
Soft Matter | Year: 2010

We report the complexation of a potential anticancer agent 2-methoxyestradiol (2-ME) with generation 5 (G5) poly(amidoamine) dendrimers having different surface functional groups for therapeutic applications. The complexation experiment shows that approximately 6-8 drug molecules can be complexed with one dendrimer molecule regardless the type of the dendrimer terminal groups. The bioactivity of 2-ME complexed with dendrimers was found to be significantly dependent on the surface charge of G5 dendrimers. In vitro cell biological assays show that amine, hydroxyl, and acetamide-terminated G5 dendrimers with positive, slightly positive, and close to neutral surface charges, respectively are able to deliver 2-ME to inhibit cancer cell growth. In contrast, 2-ME complexed with carboxyl-terminated G5 dendrimers with negative surface charges does not show its inherent bioactivity. Further molecular dynamics simulation studies show that the compact structure of carboxylated G5 dendrimers complexed with 2-ME does not allow the release of the drug molecules even at a pH of 5.0, which is the typical pH value in lysosome. Our findings indicate that the surface modification of dendrimers with different charges is crucial for the development of formulations of various anticancer drugs for therapeutic applications. © 2010 The Royal Society of Chemistry. Source


Kim N.H.,Yonsei University | Cha Y.H.,Yonsei University | Kang S.E.,Yonsei University | Lee Y.,Yonsei University | And 9 more authors.
Cell Cycle | Year: 2013

p53 is a bona fide tumor suppressor gene whose loss of function marks the most common genetic alteration in human malignancy. Although the causal link between loss of p53 function and tumorigenesis has been clearly demonstrated, the mechanistic links by which loss of p53 potentiates oncogenic signaling are not fully understood. Recent evidence indicates that the microRNA-34 (miR-34) family, a transcriptional target of the p53, directly suppresses a set of canonical Wnt genes and Snail, resulting in p53-mediated suppression of Wnt signaling and the EMT process. In this study, we report that p53 regulates GSK-3β nuclear localization via miR-34-mediated suppression of Axin2 in colorectal cancer. Exogenous miR-34a decreases Axin2 UTR-reporter activity through multiple binding sites within the 5′ and 3′ UTR of Axin2. Suppression of Axin2 by p53 or miR-34 increases nuclear GSK-3β abundance and leads to decreased Snail expression in colorectal cancer cells. Conversely, expression of the non-coding UTR of Axin2 causes depletion of endogenous miR-34 via the miR-sponge effect together with increased Axin2 function, supporting that the RNA-RNA interactions with Axin2 transcripts act as an endogenous decoy for miR-34. Further, RNA transcripts of miR-34 target were correlated with Axin2 in clinical data set of colorectal cancer patients. Although the biological relevance of nuclear GSK-3 level has not been fully studied, our results demonstrate that the tumor suppressor p53/miR-34 axis plays a role in regulating nuclear GSK-3 levels and Wnt signaling through the non-coding UTR of Axin2 in colorectal cancer. © 2013 Landes Bioscience. Source


Lee K.-H.,University of Michigan | Lee I.,miRcore | Baker Jr. J.R.,University of Michigan | Holl M.M.B.,University of Michigan
Journal of Computational and Theoretical Nanoscience | Year: 2012

Molecular dynamics (MD) simulations on G3 poly(amidoamine) (PAMAM) dendrons bearing an alkyne focal point were carried out at three different pH levels and with explicit water and counterions to obtain appropriate simulation conditions and validity for waterless simulations. We find that charged dendron simulation results with distance-dependent dielectric constant without nonbonded cutoff distance are most similar to the ones in explicit water and counterions. Structural changes of PAMAM dendrons and focal point accessibility are understood as functions of pH and dendron generation using MD simulations with the long-range interaction parameters. The simulation results indicate that the radii of gyration of the G3 and G5 dendrons at low pH (≤ 4) increase ∼67% as compared with those at high pH (≥ 10) and neutral pH (∼7). The dendron structures exhibit an increasingly hollow interior as pH level decreases. The dendron focal point remained accessible for all generations and pH values studied. © 2012 American Scientific Publishers. All rights reserved. Source

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