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https://www.readbyqxmd.com/read/28702009/crm1-inhibitors-for-antiviral-therapy
#1
REVIEW
Cynthia Mathew, Reena Ghildyal
Infectious diseases are a major global concern and despite major advancements in medical research, still cause significant morbidity and mortality. Progress in antiviral therapy is particularly hindered by appearance of mutants capable of overcoming the effects of drugs targeting viral components. Alternatively, development of drugs targeting host proteins essential for completion of viral lifecycle holds potential as a viable strategy for antiviral therapy. Nucleocytoplasmic trafficking pathways in particular are involved in several pathological conditions including cancer and viral infections, where hijacking or alteration of function of key transporter proteins, such as Chromosome Region Maintenance1 (CRM1) is observed...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28689976/crm1-inhibitory-and-antiproliferative-activities-of-novel-4-alkyl-substituted-klavuzon-derivatives
#2
Tuğçe Kanbur, Murat Kara, Meltem Kutluer, Ayhan Şen, Murat Delman, Aylin Alkan, Hasan Ozan Otaş, İsmail Akçok, Ali Çağır
Klavuzons are 6-(naphthalen-1-yl) substituted 5,6-dihydro-2H-pyran-2-one derivatives showing promising antiproliferative activities in variety of cancer cell lines. In this work, racemic syntheses of nine novel 4'-alkyl substituted klavuzon derivatives were completed in eight steps and anticancer properties of these compounds were evaluated. It is found that size of the substituent has dramatic effect over the potency and selectivity of the cytotoxic activity in cancerous and healthy pancreatic cell lines. The size of the substituent can also effect the CRM1 inhibitory properties of klavuzon derivatives...
June 19, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28600321/importin-beta-and-crm1-control-a-ranbp2-spatiotemporal-switch-essential-for-mitotic-kinetochore-function
#3
Eugenia Gilistro, Valeria de Turris, Michela Damizia, Annalisa Verrico, Sara Moroni, Riccardo De Santis, Alessandro Rosa, Patrizia Lavia
Protein conjugation with SUMO is a post-translational modification that modulates protein interactions and localisation. RANBP2 is a large nucleoporin endowed with SUMO E3 ligase and SUMO-stabilising activity and is implicated in some cancer types. RANBP2 is part of a larger complex, comprising SUMO-modified RANGAP1, the GTP-hydrolysis activating factor for the GTPase RAN. During mitosis, the RANBP2/SUMO-RANGAP1 complex localises to the mitotic spindle and to kinetochores after microtubule attachment. Here we have addressed the mechanisms that regulate this localisation and how they affect kinetochore functions...
June 9, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28582471/sumo-regulates-p21cip1-intracellular-distribution-and-with-p21cip1-facilitates-multiprotein-complex-formation-in-the-nucleolus-upon-dna-damage
#4
Sonia Brun, Neus Abella, Maria T Berciano, Olga Tapia, Montserrat Jaumot, Raimundo Freire, Miguel Lafarga, Neus Agell
We previously showed that p21Cip1 transits through the nucleolus on its way from the nucleus to the cytoplasm and that DNA damage inhibits this transit and induces the formation of p21Cip1-containing intranucleolar bodies (INoBs). Here, we demonstrate that these INoBs also contain SUMO-1 and UBC9, the E2 SUMO-conjugating enzyme. Furthermore, whereas wild type SUMO-1 localized in INoBs, a SUMO-1 mutant, which is unable to conjugate with proteins, does not, suggesting the presence of SUMOylated proteins at INoBs...
2017: PloS One
https://www.readbyqxmd.com/read/28515232/the-nuclear-export-factor-crm1-controls-juxta-nuclear-microtubule-dependent-virus-transport
#5
I-Hsuan Wang, Christoph J Burckhardt, Artur Yakimovich, Matthias K Morf, Urs F Greber
Transport of large cargo through the cytoplasm requires motor proteins and polarized filaments. Viruses that replicate in the nucleus of post-mitotic cells use microtubules and the dynein-dynactin motor to traffic to the nuclear membrane and deliver their genome through nuclear pore complexes (NPCs) into the nucleus. How virus particles (virions) or cellular cargo are transferred from microtubules to the NPC is unknown. Here, we analyzed trafficking of incoming cytoplasmic adenoviruses by single-particle tracking and super-resolution microscopy...
July 1, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28490361/adducin-family-proteins-possess-different-nuclear-export-potentials
#6
Chia-Mei Liu, Wen-Hsin Hsu, Wan-Yi Lin, Hong-Chen Chen
BACKGROUND: The adducin (ADD) family proteins, namely ADD1, ADD2, and ADD3, are actin-binding proteins that play important roles in the stabilization of membrane cytoskeleton and cell-cell junctions. All the ADD proteins contain a highly conserved bipartite nuclear localization signal (NLS) at the carboxyl termini, but only ADD1 can localize to the nucleus. The reason for this discrepancy is not clear. METHODS: To avoid the potential effect of cell-cell junctions on the distribution of ADD proteins, HA epitope-tagged ADD proteins and mutants were transiently expressed in NIH3T3 fibroblasts and their distribution in the cytoplasm and nucleus was examined by immunofluorescence staining...
May 10, 2017: Journal of Biomedical Science
https://www.readbyqxmd.com/read/28463106/nuclear-export-of-misfolded-sod1-mediated-by-a-normally-buried-nes-like-sequence-reduces-proteotoxicity-in-the-nucleus
#7
Yongwang Zhong, Jiou Wang, Mark J Henderson, Peixin Yang, Brian M Hagen, Teepu Siddique, Bruce E Vogel, Han-Xiang Deng, Shengyun Fang
Over 170 different mutations in the gene encoding SOD1 all cause amyotrophic lateral sclerosis (ALS). Available studies have been primarily focused on the mechanisms underlying mutant SOD1 cytotoxicity. How cells defend against the cytotoxicity remains largely unknown. Here, we show that misfolding of ALS-linked SOD1 mutants and wild-type (wt) SOD1 exposes a normally buried nuclear export signal (NES)-like sequence. The nuclear export carrier protein CRM1 recognizes this NES-like sequence and exports misfolded SOD1 to the cytoplasm...
May 2, 2017: ELife
https://www.readbyqxmd.com/read/28450420/validation-identification-and-biological-consequences-of-the-site-specific-o-glcnacylation-dynamics-of-carbohydrate-responsive-element-binding-protein-chrebp
#8
An-Qi Yang, Daoyuan Li, Lianli Chi, Xin-Shan Ye
O-GlcNAcylation of carbohydrate-responsive element-binding protein (ChREBP) is believed as an important modulator of ChREBP activities, however little direct evidence of O-GlcNAcylation on ChREBP and no exact O-GlcNAcylation sites have been reported so far. Here, we validate O-GlcNAcylation on ChREBP in cell-free coupled transcription/translation system and in cells by chemoenzymatic and metabolic labeling, respectively. Moreover, for the first time, we identify O-GlcNAcylation on Ser614 in the C-terminus of ChREBP by mass spectrometry and validate two important sites, Thr517 and Ser839 for O-GlcNAcylation and their function via molecular and chemical biological method...
July 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28412356/leptomycin-b-alters-the-subcellular-distribution-of-crm1-exportin-1
#9
Khatera Rahmani, David A Dean
CRM1 (chromosome maintenance region 1, Exportin 1) binds to nuclear export signals and is required for nucleocytoplasmic transport of a large variety of proteins and RNP complexes. Leptomycin B (LMB), the first specific inhibitor of CRM1 identified, binds covalently to cysteine 528 in the nuclear export signal binding region of CRM1 leading to the inhibition of protein nuclear export. Although the biochemical mechanisms of action of CRM1 inhibitors such as LMB are well studied, the subcellular effects of inhibition on CRM1 are unknown...
April 12, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28399435/inhibition-of-crm1-mediated-nuclear-export-of-influenza-a-nucleoprotein-and-nuclear-export-protein-as-a-novel-target-for-antiviral-drug-development
#10
Nopporn Chutiwitoonchai, Takafumi Mano, Michinori Kakisaka, Hirotaka Sato, Yasumitsu Kondoh, Hiroyuki Osada, Osamu Kotani, Masaru Yokoyama, Hironori Sato, Yoko Aida
An anti-influenza compound, DP2392-E10 based on inhibition of the nuclear export function of the viral nucleoprotein-nuclear export signal 3 (NP-NES3) domain was successfully identified by our previous high-throughput screening system. Here, we demonstrated that DP2392-E10 exerts its antiviral effect by inhibiting replication of a broad range of influenza A subtypes. In regard to the molecular mechanism, we revealed that DP2392-E10 inhibits nuclear export of both viral NP and nuclear export protein (NEP). More specifically, in vitro pull-down assays revealed that DP2392-E10 directly binds cellular CRM1, which mediates nuclear export of NP and NEP...
July 2017: Virology
https://www.readbyqxmd.com/read/28373767/expression-of-crm1-and-cdk5-shows-high-prognostic-accuracy-for-gastric-cancer
#11
Yu-Qin Sun, Jian-Wei Xie, Hong-Teng Xie, Peng-Chen Chen, Xiu-Li Zhang, Chao-Hui Zheng, Ping Li, Jia-Bin Wang, Jian-Xian Lin, Long-Long Cao, Chang-Ming Huang, Yao Lin
AIM: To evaluate the predictive value of the expression of chromosomal maintenance (CRM)1 and cyclin-dependent kinase (CDK)5 in gastric cancer (GC) patients after gastrectomy. METHODS: A total of 240 GC patients who received standard gastrectomy were enrolled in the study. The expression level of CRM1 and CDK5 was detected by immunohistochemistry. The correlations between CRM1 and CDK5 expression and clinicopathological factors were explored. Univariate and multivariate survival analyses were used to identify prognostic factors for GC...
March 21, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28341984/combinatorial-requirement-of-w-and-wt-boxes-in-microbe-associated-molecular-pattern-responsive-synthetic-promoters
#12
Konstantin Kanofsky, Ann-Kathrin Bahlmann, Reinhard Hehl, Do Xuan Dong
The WT-box GGACTTTC belongs to a novel class of MAMP-responsive cis-regulatory sequences that are part of combinatorial elements. Microbe-associated molecular pattern (MAMP)-responsive synthetic promoters were generated with two cis-regulatory modules (CRM1 and CRM2) from the Arabidopsis thaliana WRKY30 promoter. Both modules harbour two W-boxes and one WT-box. Mutation analysis of the synthetic promoters and transient gene expression analysis in parsley protoplasts underline the importance of the W- and WT-boxes for MAMP-responsive gene expression and reveal the combinatorial requirement of at least two boxes for full MAMP responsivity...
March 24, 2017: Plant Cell Reports
https://www.readbyqxmd.com/read/28334815/gcn5-mediated-rph1-acetylation-regulates-its-autophagic-degradation-under-dna-damage-stress
#13
Feng Li, Liang-De Zheng, Xin Chen, Xiaolu Zhao, Scott D Briggs, Hai-Ning Du
Histone modifiers regulate proper cellular activities in response to various environmental stress by modulating gene expression. In budding yeast, Rph1 transcriptionally represses many DNA damage or autophagy-related gene expression. However, little is known how Rph1 is regulated during these stress conditions. Here, we report that Rph1 is degraded upon DNA damage stress conditions. Notably, this degradation occurs via the autophagy pathway rather than through 26S proteasome proteolysis. Deletion of ATG genes or inhibition of vacuole protease activity compromises Rph1 turnover...
May 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28326644/hiv-1-susceptibility-of-transgenic-rat-derived-primary-macrophage-t-cells-and-a-t-cell-line-that-express-human-receptors-cyclint1-and-crm1-genes
#14
Hisatoshi Shida, Hiroyuki Okada, Hajime Suzuki, Xianfeng Zhang, Jing Chen, Yasuko Tsunetsugu-Yokota, Yuetsu Tanaka, Fumika Yakushiji, Yoshio Hayashi
We developed transgenic (Tg) rats that express human CD4, CCR5, CXCR4, CyclinT1, and CRM1 genes. Tg rat macrophages were efficiently infected with HIV-1 and supported production of infectious progeny virus. By contrast, both rat primary CD4(+) T cells and established T cell lines expressing human CD4, CCR5, CyclinT1, and CRM1 genes were infected inefficiently, but this was ameliorated by inhibition of cyclophilin A. The infectivity of rat T cell-derived virus was lower than that of human T cell-derived virus...
May 2017: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/28325843/a-biochemical-framework-for-eif4e-dependent-mrna-export-and-nuclear-recycling-of-the-export-machinery
#15
Laurent Volpon, Biljana Culjkovic-Kraljacic, Hye Seon Sohn, Alexis Blanchet-Cohen, Michael J Osborne, Katherine L B Borden
The eukaryotic translation initiation factor eIF4E acts in the nuclear export and translation of a subset of mRNAs. Both of these functions contribute to its oncogenic potential. While the biochemical mechanisms that underlie translation are relatively well understood, the molecular basis for eIF4E's role in mRNA export remains largely unexplored. To date, over 3000 transcripts, many encoding oncoproteins, were identified as potential nuclear eIF4E export targets. These target RNAs typically contain a ∼50-nucleotide eIF4E sensitivity element (4ESE) in the 3' UTR and a 7-methylguanosine cap on the 5' end...
June 2017: RNA
https://www.readbyqxmd.com/read/28287257/inhibition-of-multimolecular-rna-protein-interactions-using-multitarget-directed-nanohybrid-system
#16
Woo-Jin Jeong, Mahnseok Kye, So-Hee Han, Jun Shik Choi, Yong-Beom Lim
Multitarget-directed ligands (MTDLs) are hybrid ligands obtained by covalently linking active pharmacophores that can act on different targets. We envision that the concept of MTDLs can also be applied to supramolecular bioinorganic nanohybrid systems. Here, we report the inhibition of multimolecular RNA-protein complexes using multitarget-directed peptide-carbon nanotube hybrids (SPCHs). One of the most well-characterized and important RNA-protein interactions, a Rev-response element (RRE) RNA:Rev protein:Crm1 protein interaction system in human immunodeficiency virus type-1, was used as a model of multimolecular RNA-protein interactions...
April 5, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28286054/chromosome-region-maintenance-1-crm1-regulates-apoptosis-of-intestinal-epithelial-cells-via-p27kip1-in-crohn-s-disease
#17
Lijun Yan, Liang Wang, Jian'an Bai, Xianjing Miao, Weiwen Zeng, Xiumei Hua, Runzhou Ni, Dongmei Zhang, Qiyun Tang
OBJECTIVE: To investigate the role of chromosome region maintenance-1 (CRM1) in Crohn's disease (CD) and its potential pathological mechanisms. METHODS: The expression and distribution of CRM1 in mucosal biopsies from patients with active CD and normal controls were detected by immunohistochemistry (IHC). We established a murine model of acute colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). Western blot was performed to investigate the expression levels of CRM1, apoptotic markers (active caspase-3 and cleaved PARP), p27kip1 and p-p27ser10...
March 9, 2017: Clinics and Research in Hepatology and Gastroenterology
https://www.readbyqxmd.com/read/28282025/nuclear-export-receptor-crm1-recognizes-diverse-conformations-in-nuclear-export-signals
#18
Ho Yee Joyce Fung, Szu-Chin Fu, Yuh Min Chook
Nuclear export receptor CRM1 binds highly variable nuclear export signals (NESs) in hundreds of different cargoes. Previously we have shown that CRM1 binds NESs in both polypeptide orientations (Fung et al., 2015). Here, we show crystal structures of CRM1 bound to eight additional NESs which reveal diverse conformations that range from loop-like to all-helix, which occupy different extents of the invariant NES-binding groove. Analysis of all NES structures show 5-6 distinct backbone conformations where the only conserved secondary structural element is one turn of helix that binds the central portion of the CRM1 groove...
March 10, 2017: ELife
https://www.readbyqxmd.com/read/28219018/selective-incorporation-of-vrnp-into-influenza-a-virions-determined-by-its-specific-interaction-with-m1-protein
#19
Chutikarn Chaimayo, Tsuyoshi Hayashi, Andrew Underwood, Erin Hodges, Toru Takimoto
Influenza A viruses contain eight single-stranded, negative-sense RNA segments as viral genomes in the form of viral ribonucleoproteins (vRNPs). During genome replication in the nucleus, positive-sense complementary RNPs (cRNPs) are produced as replicative intermediates, which are not incorporated into progeny virions. To analyze the mechanism of selective vRNP incorporation into progeny virions, we quantified vRNPs and cRNPs in the nuclear and cytosolic fractions of infected cells, using a strand-specific qRT-PCR...
May 2017: Virology
https://www.readbyqxmd.com/read/28216671/dual-mechanisms-regulate-the-nucleocytoplasmic-localization-of-human-ddx6
#20
Jo-Hsi Huang, Wei-Chi Ku, Yen-Chun Chen, Yi-Ling Chang, Chia-Ying Chu
DDX6 is a conserved DEAD-box protein (DBP) that plays central roles in cytoplasmic RNA regulation, including processing body (P-body) assembly, mRNA decapping, and translational repression. Beyond its cytoplasmic functions, DDX6 may also have nuclear functions because its orthologues are known to localize to nuclei in several biological contexts. However, it is unclear whether DDX6 is generally present in human cell nuclei, and the molecular mechanism underlying DDX6 subcellular distribution remains elusive...
February 20, 2017: Scientific Reports
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