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Human-yeast genetic interaction for disease network: systematic discovery of multiple drug targets
( Kyoungho Suk ) 생화학분자생물학회(구 한국생화학분자생물학회) 2017 BMB Reports Vol.50 No.11
A novel approach has been used to identify functional interactions relevant to human disease. Using high-throughput human-yeast genetic interaction screens, a first draft of disease interactome was obtained. This was achieved by first searching for candidate human disease genes that confer toxicity in yeast, and second, identifying modulators of toxicity. This study found potentially disease-relevant interactions by analyzing the network of functional interactions and focusing on genes implicated in amyotrophic lateral sclerosis (ALS), for example. In the subsequent proof-of-concept study focused on ALS, similar functional relationships between a specific kinase and ALS-associated genes were observed in mammalian cells and zebrafish, supporting findings in human-yeast genetic interaction screens. Results of combined analyses highlighted MAP2K5 kinase as a potential therapeutic target in ALS. [BMB Reports: Perspective 2017; 50(11): 535-536]
Differences between TLR2 and TLR4 signalings in microglial apoptosis
Suk, Kyoungho 이화여자대학교 세포신호전달연구센터 2006 고사리 세포신호전달 심포지움 Vol. No.8
TLRs mediate diverse signaling after recognition of evolutionary conserved pathogen-associated molecular patterns(PAMP) such as LPS and lipopeptides. Both TLR2 and TLR4 are known to trigger a protective immune response as well as cellular apoptosis. Here, we present evidence that TLR4, but not TLR2, mediates an auto-regulatory apoptosis of activated microglia. Brain microglia underwent apoptosis upon stimulation with TLR4 ligand(LPS), but not TLR2 ligands(Pam₃Cys-Ser-Lys₄, peptidoglycan, and lipoteichoic acid). Based on studies using TLR2-deficient or TLR4 mutant mice and TLR dominant negative mutants, we also demonstrated that TLR4, but not TLR2, is necessary for microglial apoptosis. The critical difference between TLR2 and TLR4 signalings in microglia was IRF-3 activation followed by IFN-beta expression: while TLR4 agonist induced the activation of IRF-3/IFN-beta pathway, TLR2 did not. Nevertheless, both TLR2 and TLR4 agonists strongly induced NF-kB activation and nitric oxide production in microglia. Neutralizing antibody against IFN-beta attenuated TLR4-mediated microglial apoptosis. IFN-beta alone, however, did not induce a significant cell death. Meanwhile, TLR2 activation induced microglial apoptosis with a help of IFN-beta, indicating that IFN-beta production following IRF-3 activation determines the apoptogenic action of TLR signaling. TLR4-mediated microglial apoptosis was mediated by MyD88 and TRIF, and was associated with caspases-11 and -3 activation rather than FADD/caspase-8 pathway. Taken together, TLR4 appears to signal a microglial apoptosis via autocrine/paracrine IFN-beta production, which may act as an apoptotic sensitizer.
Reconstitution of human RNA interference in budding yeast
Suk, Kyoungho,Choi, Jihye,Suzuki, Yo,Ozturk, Sedide B.,Mellor, Joseph C.,Wong, Koon Ho,MacKay, Joanna L.,Gregory, Richard I.,Roth, Frederick P. Oxford University Press 2011 Nucleic acids research Vol.39 No.7
<P>Although RNA-mediated interference (RNAi) is a widely conserved process among eukaryotes, including many fungi, it is absent from the budding yeast <I>Saccharomyces cerevisiae</I>. Three human proteins, Ago2, Dicer and TRBP, are sufficient for reconstituting the RISC complex <I>in vitro</I>. To examine whether the introduction of human RNAi genes can reconstitute RNAi in <I>S. cerevisiae</I>, genes encoding these three human proteins were introduced into <I>S. cerevisiae</I>. We observed both siRNA and siRNA- and RISC-dependent silencing of the target gene <I>GFP</I>. Thus, human Ago2, Dicer and TRBP can functionally reconstitute human RNAi in <I>S. cerevisiae</I>, <I>in vivo</I>, enabling the study and use of the human RNAi pathway in a facile genetic model organism.</P>
A novel functional gene selection method provides a systematic view of cell migration.
Landes Bioscience 2010 Cell adhesion & migration Vol.4 No.2
<P>Cell migration is a central process that is essential for embryonic development, wound repair, inflammatory response, homeostasis and tumor metastasis. A method of genome-wide selection based on the gain-of-function has been devised to identify novel cell migration-promoting genes in cultured cells. After the introduction of the retroviral mouse brain cDNA library into NIH3T3 mouse fibroblast cells, migration-promoted cells were selected by a three-dimensional migration assay using cell culture inserts. After five rounds of enrichment, cDNAs were retrieved from the cells that passed the selection processes. Cell migration-promoting activity was confirmed by independent migration assays for the retrieved cDNAs. Multiple cell migration-promoting genes were successfully isolated by this method. The genes identified can be used to gain a systematic view of cell migration. The gain-offunction selection method described here can be combined with RNAi-mediated loss-of-function screen or selection to be a more powerful tool for the systems biology research of cell migration.</P>
S. Karger AG 2005 Neuro-Signals Vol.14 No.1
<P>Herbal medicine has long been used to treat neural symptoms. Although the precise mechanisms of action of herbal drugs have yet to be determined, some of them have been shown to exert anti-inflammatory and/or anti-oxidant effects in a variety of peripheral systems. Now, as increasing evidence indicates that neuroglia-derived chronic inflammatory responses play a pathological role in the central nervous system, anti-inflammatory herbal medicine and its constituents are being proved to be a potent neuroprotector against various brain pathologies. Structural diversity of medicinal herbs makes them valuable source of novel lead compounds against therapeutic targets that are newly discovered by genomics, proteomics, and high-throughput screening.</P><P>Copyright © 2005 S. Karger AG, Basel</P>
Future Drugs Ltd 2010 Expert review of proteomics Vol.7 No.2
<P>Glial cells in the CNS are likely to communicate with other glial cells and neurons through secreted proteins. Glia-derived proteins also participate in neuroinflammation, which is a major component of neurodegenerative disease. Cerebrospinal fluid (CSF) is the biological fluid that best reflects the physiological or pathological conditions of the CNS. Proteins secreted from glial cells are often detected in the CSF. One of the major cellular sources of the highly abundant CSF proteins is glia. Combined analysis of secreted proteins of glial cells and CSF proteins of patients with inflammatory CNS disorders can provide new knowledge to the field of glia biology and neuron-glia interaction. The comparative analysis of the glia secretome and the CSF proteome would also facilitate the targeted proteomics-based discovery of new biomarkers for brain disease. Omics and systems biology approaches to glia and neuroinflammation will be a focus of future investigation and will enable an integrative understanding of inflammatory CNS disorders, such as neurodegenerative disease.</P>