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  • MinireviewJune 30, 2019

    0 33 1090

    Neurodevelopmental Aspects of RASopathies

    Ye Eun Kim and Seung Tae Baek

    Mol. Cells 2019; 42(6): 441-447 https://doi.org/10.14348/molcells.2019.0037
    Abstract

    Abstract : RAS gene mutations are frequently found in one third of human cancers. Affecting approximately 1 in 1,000 newborns, germline and somatic gain-of-function mutations in the components of RAS/mitogen-activated protein kinase (RAS/MAPK) pathway has been shown to cause developmental disorders, known as RASopathies. Since RAS-MAPK pathway plays essential roles in proliferation, differentiation and migration involving developmental processes, individuals with RASopathies show abnormalities in various organ systems including central nervous system. The frequently seen neurological defects are developmental delay, macrocephaly, seizures, neurocognitive deficits, and structural malformations. Some of the defects stemmed from dysregulation of molecular and cellular processes affecting early neurodevelopmental processes. In this review, we will discuss the implications of RAS-MAPK pathway components in neurodevelopmental processes and pathogenesis of RASopathies.

  • Research ArticleJune 30, 2019

    0 18 444

    Combination Therapy with a PI3K/mTOR Dual Inhibitor and Chloroquine Enhances Synergistic Apoptotic Cell Death in Epstein–Barr Virus-Infected Gastric Cancer Cells

    Mi-Young Kim, Annie J. Kruger, Ju-Yeon Jeong, Jaehee Kim, Phil kyung Shin, Sun Young Kim, Joo Young Cho, Ki Baik Hahm, and Sung Pyo Hong

    Mol. Cells 2019; 42(6): 448-459 https://doi.org/10.14348/molcells.2019.2395
    Abstract

    Abstract : The phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway is a promising target for gastric cancer (GC) treatment; however the efficacy of PI3K/mTOR dual inhibitors in GC has not yet been maximized. Additionally, the effect of autophagy regulation by PI3K/mTOR dual inhibitors has not been clearly elucidated in GC treatment. We aimed to show that our newly developed PI3K/mTOR dual inhibitor, CMG002, when combined with an autophagy inhibitor, chloroquine (CQ), potently induces effective cancer cell death in Epstein–Barr virus (EBV)-associated gastric cancer (EBVaGC) cells, where both the PI3K/AKT/mTOR and autophagy pathways play important roles in disease pathogenesis. EBV- and mock-infected AGS and NUGC3 GC cell lines were treated with CMG002 +/− CQ. PI3K/AKT/mTOR signaling pathway mediators, cellular apoptosis and autophagy markers were confirmed by Western blot assay. Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay. CMG002 effectively blocked the PI3K/AKT/mTOR pathway by markedly decreasing phosphorylation of AKT and its downstream mediator S6. CMG002 induced G0/G1 cell cycle arrest and enhanced apoptotic cell death in AGS and NUGC3 cells, particularly EBV-infected cells compared with mock-infected cells, as confirmed by flow cytometric analyses and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assays. The combination of CMG002 plus CQ synergistically increased apoptotic cell death in EBV-infected GC cell lines when compared with CMG002 alone (P < 0.05). Our results suggest that the new PI3K/mTOR dual inhibitor, CMG002, when used in combination with the autophagy inhibitor, CQ, provides enhanced therapeutic efficacy against EBVaGC.

  • Research ArticleJune 30, 2019

    0 19 383

    Crystal Structure of a Highly Thermostable α-Carbonic Anhydrase from Persephonella marina EX-H1

    Subin Kim, Jongmin Sung, Jungyoon Yeon, Seung Hun Choi, and Mi Sun Jin

    Mol. Cells 2019; 42(6): 460-469 https://doi.org/10.14348/molcells.2019.0029
    Abstract

    Abstract : Bacterial α-type carbonic anhydrase (α-CA) is a zinc metalloenzyme that catalyzes the reversible and extremely rapid interconversion of carbon dioxide to bicarbonate. In this study, we report the first crystal structure of a hyperthermostable α-CA from Persephonella marina EX-H1 (pmCA) in the absence and presence of competitive inhibitor, acetazolamide. The structure reveals a compactly folded pmCA homodimer in which each monomer consists of a 10-stranded β-sheet in the center. The catalytic zinc ion is coordinated by three highly conserved histidine residues with an exchangeable fourth ligand (a water molecule, a bicarbonate anion, or the sulfonamide group of acetazolamide). Together with an intramolecular disulfide bond, extensive interfacial networks of hydrogen bonds, ionic and hydrophobic interactions stabilize the dimeric structure and are likely responsible for the high thermal stability. We also identified novel binding sites for calcium ions at the crystallographic interface, which serve as molecular glue linking negatively charged and otherwise repulsive surfaces. Furthermore, this large negatively charged patch appears to further increase the thermostability at alkaline pH range via favorable charge-charge interactions between pmCA and solvent molecules. These findings may assist development of novel α-CAs with improved thermal and/or alkaline stability for applications such as CO2 capture and sequestration.

  • Research ArticleJune 30, 2019

    0 25 277
    Abstract

    Abstract : Interstitial cells of Cajal (ICCs) are pacemaker cells that exhibit periodic spontaneous depolarization in the gastrointestinal (GI) tract and generate pacemaker potentials. In this study, we investigated the effects of ghrelin and motilin on the pacemaker potentials of ICCs isolated from the mouse small intestine. Using the whole-cell patch-clamp configuration, we demonstrated that ghrelin depolarized pacemaker potentials of cultured ICCs in a dose-dependent manner. The ghrelin receptor antagonist [D-Lys] GHRP-6 completely inhibited this ghrelin-induced depolarization. Intracellular guanosine 5′-diphosphate-β-S and pre-treatment with Ca2+-free solution or thapsigargin also blocked the ghrelin-induced depolarization. To investigate the involvement of inositol triphosphate (IP3), Rho kinase, and protein kinase C (PKC) in ghrelin-mediated pacemaker potential depolarization of ICCs, we used the IP3 receptor inhibitors 2-aminoethoxydiphenyl borate and xestospongin C, the Rho kinase inhibitor Y-27632, and the PKC inhibitors staurosporine, Go6976, and rottlerin. All inhibitors except rottlerin blocked the ghrelin-induced pacemaker potential depolarization of ICCs. In addition, motilin depolarized the pacemaker potentials of ICCs in a similar dose-dependent manner as ghrelin, and this was also completely inhibited by [D-Lys] GHRP-6. These results suggest that ghrelin induced the pacemaker potential depolarization through the ghrelin receptor in a G protein-, IP3-, Rho kinase-, and PKC-dependent manner via intracellular and extracellular Ca2+ regulation. In addition, motilin was able to depolarize the pacemaker potentials of ICCs through the ghrelin receptor. Therefore, ghrelin and its receptor may modulate GI motility by acting on ICCs in the murine small intestine.

  • Research ArticleJune 30, 2019

    0 15 551

    Cell-Based Screen Using Amyloid Mimic β23 Expression Identifies Peucedanocoumarin III as a Novel Inhibitor of α-Synuclein and Huntingtin Aggregates

    Sangwoo Ham, Hyojung Kim, Seojin Hwang, Hyunook Kang, Seung Pil Yun, Sangjune Kim, Donghoon Kim, Hyun Sook Kwon, Yun-Song Lee, MyoungLae Cho, Heung-Mook Shin, Heejung Choi, Ka Young Chung, Han Seok Ko, Gum Hwa Lee, and Yunjong Lee

    Mol. Cells 2019; 42(6): 480-494 https://doi.org/10.14348/molcells.2019.0091
    Abstract

    Abstract : Aggregates of disease-causing proteins dysregulate cellular functions, thereby causing neuronal cell loss in diverse neurodegenerative diseases. Although many in vitro or in vivo studies of protein aggregate inhibitors have been performed, a therapeutic strategy to control aggregate toxicity has not been earnestly pursued, partly due to the limitations of available aggregate models. In this study, we established a tetracycline (Tet)-inducible nuclear aggregate (β23) expression model to screen potential lead compounds inhibiting β23-induced toxicity. High-throughput screening identified several natural compounds as nuclear β23 inhibitors, including peucedanocoumarin III (PCIII). Interestingly, PCIII accelerates disaggregation and proteasomal clearance of both nuclear and cytosolic β23 aggregates and protects SH-SY5Y cells from toxicity induced by β23 expression. Of translational relevance, PCIII disassembled fibrils and enhanced clearance of cytosolic and nuclear protein aggregates in cellular models of huntingtin and α-synuclein aggregation. Moreover, cellular toxicity was diminished with PCIII treatment for polyglutamine (PolyQ)-huntingtin expression and α-synuclein expression in conjunction with 6-hydroxydopamine (6-OHDA) treatment. Importantly, PCIII not only inhibited α-synuclein aggregation but also disaggregated preformed α-synuclein fibrils in vitro. Taken together, our results suggest that a Tet-Off β23 cell model could serve as a robust platform for screening effective lead compounds inhibiting nuclear or cytosolic protein aggregates. Brain-permeable PCIII or its derivatives could be beneficial for eliminating established protein aggregates.

  • Research ArticleJune 30, 2019

    0 24 230

    Heterogeneous Sequences of Brain Cytoplasmic 200 RNA Formed by Multiple Adenine Nucleotide Insertions

    Heegwon Shin, Jungmin Lee, Youngmi Kim, Seonghui Jang, Meehyein Kim, and Younghoon Lee

    Mol. Cells 2019; 42(6): 495-500 https://doi.org/10.14348/molcells.2019.0108
    Abstract

    Abstract : Brain cytoplasmic 200 RNA (BC200 RNA), originally identified as a neuron-specific non-coding RNA, is also observed in various cancer cells that originate from non-neural cells. Studies have revealed diverse functions of BC200 RNA in cancer cells. Accordingly, we hypothesized that BC200 RNA might be modified in cancer cells to generate cancerous BC200 RNA responsible for its cancer-specific functions. Here, we report that BC200 RNA sequences are highly heterogeneous in cancer cells by virtue of multiple adenine nucleotide insertions in the internal A-rich region. The insertion of adenine nucleotides enhances BC200 RNA-mediated translation inhibition, possibly by increasing the binding affinity of BC200 RNA for eIF4A (eukaryotic translation initiation factor 4A).

  • ErratumJune 30, 2019

    0 15 176
Mol. Cells
Nov 30, 2021 Vol.44 No.11
COVER PICTURE
3D quantitative images of the vesicular structure and the nucleolus using label free optical diffraction tomography (Kim et al., pp. 851-860).

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