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https://www.readbyqxmd.com/read/28628637/survival-bacterial-clearance-and-thrombocytopenia-are-improved-in-polymicrobial-sepsis-by-targeting-nuclear-transport-shuttles
#1
Ruth Ann Veach, Yan Liu, Jozef Zienkiewicz, Lukasz S Wylezinski, Kelli L Boyd, James L Wynn, Jacek Hawiger
The rising tide of sepsis, a leading cause of death in the US and globally, is not adequately controlled by current antimicrobial therapies and supportive measures, thereby requiring new adjunctive treatments. Severe microvascular injury and multiple organ failure in sepsis are attributed to a "genomic storm" resulting from changes in microbial and host genomes encoding virulence factors and endogenous inflammatory mediators, respectively. This storm is mediated by stress-responsive transcription factors that are ferried to the nucleus by nuclear transport shuttles importins/karyopherins...
2017: PloS One
https://www.readbyqxmd.com/read/28621822/cdna-microarray-analysis-identifies-nr4a2-as-a-novel-molecule-involved-in-the-pathogenesis-of-sj%C3%A3-gren-s-syndrome
#2
Hiroyuki Takahashi, Hiroto Tsuboi, Hiromitsu Asashima, Tomoya Hirota, Yuya Kondo, Masafumi Moriyama, Isao Matsumoto, Seiji Nakamura, Takayuki Sumida
OBJECTIVE: To examine genes expressed specifically in labial salivary glands (LSGs) of patients with Sjögren's syndrome (SS) in comparison with those of patients with IgG4-related disease (IgG4-RD) and to identify the genes involved in the pathogenesis of SS. METHODS: Gene expression in LSGs of SS patients, IgG4-RD patients and healthy controls (HC) was analyzed by cDNA microarray. Quantitative PCR (qPCR) was used to validate the up-regulation of differentially expressed genes (DEGs) in SS...
June 16, 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28611287/vorinostat-suppresses-hypoxia-signaling-by-modulating-nuclear-translocation-of-hypoxia-inducible-factor-1-alpha
#3
Chao Zhang, Chunzhang Yang, Michael J Feldman, Herui Wang, Ying Pang, Dominic M Maggio, Dongwang Zhu, Cody L Nesvick, Pauline Dmitriev, Petra Bullova, Prashant Chittiboina, Roscoe O Brady, Karel Pacak, Zhengping Zhuang
Histone deacetylase inhibitors (HDACis) are a potent class of tumor-suppressive agents traditionally believed to exert their effects through loosening tightly-wound chromatin resulting in de-inhibition of various tumor suppressive genes. Recent literature however has shown altered intratumoral hypoxia signaling with HDACi administration not attributable to changes in chromatin structure. We sought to determine the precise mechanism of HDACi-mediated hypoxia signaling attenuation using vorinostat (SAHA), an FDA-approved class I/IIb/IV HDACi...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28600962/determination-of-the-binding-site-of-2-aminothiazole-derivative-with-importin-%C3%AE-1-by-uv-crosslinking-experiment
#4
Siyoung Ha, Jiwon Oh, Yong-Hak Kim, Seung Wook Ham
Importin β1 (KPBN1) appears to be overexpressed in several cancer cells and siRNA-induced inhibition of KPNB1 shows significant inhibition of cancer cell proliferation, but do not affect normal cells. These results indicate that KPNB1 is a potential target and inhibition of KPNB1 can be used as a novel therapeutic approach for the treatment of cancer. Recently, we identified the aminothiazole derivative 1 as a KPNB1-targeted anticancer agent. Herein, we report that compound 1 binds strongly to KPNB1, in a pocket centered around serine-476, as shown by UV-crosslinking and tandem mass spectrometry experiments, and supported using a model derived from molecular docking...
June 3, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28600321/importin-beta-and-crm1-control-a-ranbp2-spatiotemporal-switch-essential-for-mitotic-kinetochore-function
#5
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/28598151/active-targeting-of-the-nucleus-using-non-peptidic-boronate-tags
#6
Rui Tang, Ming Wang, Moumita Ray, Ying Jiang, Ziwen Jiang, Qiaobing Xu, Vincent M Rotello
Active intracellular transport is a central mechanism in cell biology, directed by a limited set of naturally occurring signaling peptides. Here we report the first non-peptide moiety that recruits intracellular transport machinery for nuclear targeting. Proteins synthetically modified with a simple aromatic boronate motif are actively trafficked to the nucleus via the importin α/β pathway. Significantly, proteins too large to passively diffuse through nuclear pores were readily imported into the nucleus through this boronate-mediated pathway...
June 9, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28595092/ebolavirus-protein-vp24-interferes-with-innate-immune-responses-by-inhibiting-interferon-%C3%AE-1-gene-expression
#7
Felix He, Krister Melén, Sari Maljanen, Rickard Lundberg, Miao Jiang, Pamela Österlund, Laura Kakkola, Ilkka Julkunen
Ebolaviruses (EBOV) cause severe disease with a recent outbreak in West Africa in 2014-2015 leading to more than 28 000 cases and 11 300 fatalities. This emphasizes the urgent need for better knowledge on these highly pathogenic RNA viruses. Host innate immune responses play a key role in restricting the spread of a viral disease. In this study we systematically analyzed the effects of cloned EBOV genes on the main host immune response to RNA viruses: the activation of RIG-I pathway and type I and III interferon (IFN) gene expression...
June 5, 2017: Virology
https://www.readbyqxmd.com/read/28572574/survive-or-thrive-tradeoff-strategy-for-cellular-senescence
#8
REVIEW
Sang Chul Park
Aging-dependent cellular behaviors toward extrinsic stress are characterized by the confined localization of certain molecules to either nuclear or perinuclear regions. Although most growth factors can activate downstream signaling in aging cells, they do not in fact have any impact on the cells because the signals cannot reach their genetic targets in the nucleus. For the same reason, varying apoptotic stress factors cannot stimulate the apoptotic pathway in senescent cells. Thus, the operation of a functional nuclear barrier in an aging-dependent manner has been investigated...
June 2, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28552616/nucleus-translocated-acss2-promotes-gene-transcription-for-lysosomal-biogenesis-and-autophagy
#9
Xinjian Li, Willie Yu, Xu Qian, Yan Xia, Yanhua Zheng, Jong-Ho Lee, Wei Li, Jianxin Lyu, Ganesh Rao, Xiaochun Zhang, Chao-Nan Qian, Steven G Rozen, Tao Jiang, Zhimin Lu
Overcoming metabolic stress is a critical step in tumor growth. Acetyl coenzyme A (acetyl-CoA) generated from glucose and acetate uptake is important for histone acetylation and gene expression. However, how acetyl-CoA is produced under nutritional stress is unclear. We demonstrate here that glucose deprivation results in AMP-activated protein kinase (AMPK)-mediated acetyl-CoA synthetase 2 (ACSS2) phosphorylation at S659, which exposed the nuclear localization signal of ACSS2 for importin α5 binding and nuclear translocation...
June 1, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28550879/reprint-of-importins-in-the-maintenance-and-lineage-commitment-of-es-cells
#10
REVIEW
Noriko Yasuhara, Yoshihiro Yoneda
The nucleus of a eukaryotic cell is separated from the cytoplasm by a nuclear envelope, and nuclear pores within the envelope facilitate nucleocytoplasmic transport and the exchange of information. Gene regulation is a key component of biological activity regulation in the cell. Transcription factors control the expression levels of various genes that are necessary for the maintenance or conversion of cellular states during animal development. Because transcription factor activities determine the extent of transcription of target genes, the number of active transcription factors must be tightly regulated...
June 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28498452/calpain-and-ar-v7-two-potential-therapeutic-targets-to-overcome-acquired-docetaxel-resistance-in-castration-resistant-prostate-cancer-cells
#11
Lei Liu, Ning Lou, Xiang Li, Guanghua Xu, Hailong Ruan, Wen Xiao, Bin Qiu, Lin Bao, Changfei Yuan, Xinmian Huang, Keshan Wang, Qi Cao, Ke Chen, Hongmei Yang, Xiaoping Zhang
Docetaxel-based chemotherapy has been widely used as the first-line treatment for castration-resistant prostate cancer (CRPC) patients. However, the mechanisms of docetaxel-resistance remain unclear. In the present study with the establishment of 2 in vitro models of docetaxel-resistant CRPC cell sublines, we firstly reported that activation of calpain may play a promotional role in the resistance of docetaxel in prostate cancer, meanwhile using the calpain inhibitor combined with docetaxel improved the efficiency of docetaxel in docetaxel-resistant cell sublines...
May 4, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28490747/structural-basis-for-importin-%C3%AE-binding-of-the-human-immunodeficiency-virus-tat
#12
K M Smith, Z Himiari, S Tsimbalyuk, J K Forwood
HIV-1 has caused 35 million deaths globally, and approximately the same number is currently living with HIV-1. The trans-activator of transcription (Tat) protein of HIV-1 plays an important regulatory function in the virus life cycle, responsible for regulating the reverse transcription of the viral genome RNA. Tat is found in the nucleus of infected cells, but can also invade uninfected neighbouring cells. Regions within Tat responsible for these cellular localisations are overlapping and include a nuclear localisation signal (NLS) spanning (48)GRKKRR, and a cell penetrating peptide (CPP) signal spanning (48)GRKKRRQRRRAPQN...
May 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28489565/motifs-in-the-amino-terminus-of-cenp-a-are-required-for-its-accumulation-within-the-nucleus-and-at-the-centromere
#13
Ruiqi Jing, Jiajie Xi, Ye Leng, Wen Chen, Guiying Wang, Wenwen Jia, Jiuhong Kang, Songcheng Zhu
Centromere protein A (CENP-A) is a variant of core histone H3 that marks the centromere's location on the chromosome. The mechanisms that target the protein to the nucleus and the centromere have not been defined. In this study, we found that deletion of the first 53 but not the first 29 residues of CENP-A from the amino-terminus, resulted in its cytoplasmic localization. Two motifs, R42R43R44 and K49R52K53K56, which are reported to be required for DNA contact in the centromere nucleosome, were found to be critical for CENP-A nuclear accumulation...
June 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28489061/microbial-natural-product-alternariol-5-o-methyl-ether-inhibits-hiv-1-integration-by-blocking-nuclear-import-of-the-pre-integration-complex
#14
Jiwei Ding, Jianyuan Zhao, Zhijun Yang, Ling Ma, Zeyun Mi, Yanbing Wu, Jiamei Guo, Jinmin Zhou, Xiaoyu Li, Ying Guo, Zonggen Peng, Tao Wei, Haisheng Yu, Liguo Zhang, Mei Ge, Shan Cen
While Highly Active Antiretroviral Therapy (HAART) has significantly decreased the mortality of human immunodeficiency virus (HIV)-infected patients, emerging drug resistance to approved HIV-1 integrase inhibitors highlights the need to develop new antivirals with novel mechanisms of action. In this study, we screened a library of microbial natural compounds from endophytic fungus Colletotrichum sp. and identified alternariol 5-O-methyl ether (AME) as a compound that inhibits HIV-1 pre-integration steps. Time-of addition analysis, quantitative real-time PCR, confocal microscopy, and WT viral replication assay were used to elucidate the mechanism...
May 10, 2017: Viruses
https://www.readbyqxmd.com/read/28398031/a-carbon-nanotube-optical-sensor-reports-nuclear-entry-via-a-noncanonical-pathway
#15
Januka Budhathoki-Uprety, Rachel E Langenbacher, Prakrit V Jena, Daniel Roxbury, Daniel A Heller
Single-walled carbon nanotubes are of interest in biomedicine for imaging and molecular sensing applications and as shuttles for various cargos such as chemotherapeutic drugs, peptides, proteins, and oligonucleotides. Carbon nanotube surface chemistry can be modulated for subcellular targeting while preserving photoluminescence for label-free visualization in complex biological environments, making them attractive materials for such studies. The cell nucleus is a potential target for many pathologies including cancer and infectious diseases...
April 25, 2017: ACS Nano
https://www.readbyqxmd.com/read/28383161/crystal-structure-of-importin-%C3%AE-bound-to-the-nuclear-localization-signal-of-epstein-barr-virus-ebna-lp-protein
#16
Ryohei Nakada, Yoshiyuki Matsuura
Epstein-Barr virus EBNA-LP protein is a transcriptional coactivator of EBNA2. Efficient nuclear localization of EBNA-LP is essential for cooperation with EBNA2. Here, we report the crystal structure of the nuclear import adaptor importin-α1 bound to the nuclear localization signal (NLS) of EBNA-LP that shows EBNA-LP residues 44-RRVRRR-49 binding to the major NLS-binding site at the P0-P5 positions. In contrast to previously characterized classical NLSs that invariably have a basic residue [either lysine (in the vast majority of cases) or arginine] at the P2 position, the EBNA-LP NLS is unique in that it has valine at the P2 position...
June 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28325843/a-biochemical-framework-for-eif4e-dependent-mrna-export-and-nuclear-recycling-of-the-export-machinery
#17
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/28316180/-effect-and-related-mechanism-of-microrna-181-attenuates-oxidized-low-density-lipoprotein-induced-vascular-endothelial-cell-injury
#18
N N Wang, X Sun, X L Zhang, L Lou, K M Chen, H Li, L Tang, W G Wang, M Zhang
Objective: To observe the expression level of microRNA-181 (miR-181) and importin-α3 in oxidized low density lipoprotein (ox-LDL) induced vascular endothelial cell injury models, and explore the effect and mechanism of miR-181 on endothelial cell injury. Methods: Human vein endothelial cell line CRL-1730 were cultured and vascular endothelial cell injury model was established by intervention with ox-LDL. The cells were divided into control group (intervened by double distilled water), low-dose group (intervened by 10 μg/ml ox-LDL) and high-dose group (intervened by 20 μg/ml ox-LDL)...
March 24, 2017: Zhonghua Xin Xue Guan Bing za Zhi
https://www.readbyqxmd.com/read/28295920/importin-%C3%AE-1-targeting-by-hepatitis-c-virus-ns3-4a-protein-restricts-irf3-and-nf-%C3%AE%C2%BAb-signaling-of-ifnb1-antiviral-response
#19
Bridget Gagné, Nicolas Tremblay, Alex Y Park, Martin Baril, Daniel Lamarre
In this study, newly identified host interactors of hepatitis C virus (HCV) proteins were assessed for a role in modulating the innate immune response. The analysis revealed enrichment for components of the nuclear transport machinery and the crucial interaction with NS3/4A protein in suppression of interferon-β (IFNB1) induction. Using a comprehensive microscopy-based high-content screening approach combined to the gene silencing of nuclear transport factors, we showed that NS3/4A-interacting proteins control the nucleocytoplasmic trafficking of IFN regulatory factor 3 (IRF3) and NF-κB p65 upon Sendai virus (SeV) infection...
March 13, 2017: Traffic
https://www.readbyqxmd.com/read/28262749/identification-of-stable-housekeeping-genes-in-response-to-ionizing-radiation-in-cancer-research
#20
Gopal Iyer, Albert R Wang, Sean R Brennan, Shay Bourgeois, Eric Armstrong, Pari Shah, Paul M Harari
Housekeeping genes (HKGs) are essential for basic maintenance of a variety of cellular processes. They ideally maintain uniform expression independent of experimental conditions. However, the effects of ionizing radiation (IR) on HKG expression is unclear. Statistical algorithms, geNorm and Normfinder were used for estimating the stability of HKGs as raw quantification cycle (Cq) values were not a reliable factor for normalization. Head and neck, non-small lung and pancreas cells were exposed to 2, 4 and 6 Gy IR doses and expression of fourteen HKGs was measured at 5 min to 48 h post-irradiation within a given tissue...
March 6, 2017: Scientific Reports
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