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https://www.readbyqxmd.com/read/28830558/identification-of-a-homogenous-structural-basis-for-oligomerization-by-retroviral-rev-like-proteins
#1
Chijioke N Umunnakwe, Karin S Dorman, Drena Dobbs, Susan Carpenter
BACKGROUND: Rev-like proteins are post-transcriptional regulatory proteins found in several retrovirus genera, including lentiviruses, betaretroviruses, and deltaretroviruses. These essential proteins mediate the nuclear export of incompletely spliced viral RNA, and act by tethering viral pre-mRNA to the host CRM1 nuclear export machinery. Although all Rev-like proteins are functionally homologous, they share less than 30% sequence identity. In the present study, we computationally assessed the extent of structural homology among retroviral Rev-like proteins within a phylogenetic framework...
August 22, 2017: Retrovirology
https://www.readbyqxmd.com/read/28791779/crystal-structure-of-the-xpo1p-nuclear-export-complex-bound-to-the-sxfg-pxfg-repeats-of-the-nucleoporin-nup42p
#2
Masako Koyama, Hidemi Hirano, Natsuki Shirai, Yoshiyuki Matsuura
Xpo1p (yeast CRM1) is the major nuclear export receptor that carries a plethora of proteins and ribonucleoproteins from the nucleus to cytoplasm. The passage of the Xpo1p nuclear export complex through nuclear pore complexes (NPCs) is facilitated by interactions with nucleoporins (Nups) containing extensive repeats of phenylalanine-glycine (so-called FG repeats), although the precise role of each Nup in the nuclear export reaction remains incompletely understood. Here we report structural and biochemical characterization of the interactions between the Xpo1p nuclear export complex and the FG repeats of Nup42p, a nucleoporin localized at the cytoplasmic face of yeast NPCs and has characteristic SxFG/PxFG sequence repeat motif...
August 8, 2017: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/28761359/nuclear-ddx3-expression-predicts-poor-outcome-in-colorectal-and-breast-cancer
#3
Marise R Heerma van Voss, Farhad Vesuna, Guus M Bol, Jan Meeldijk, Ana Raman, G Johan Offerhaus, Horst Buerger, Arvind H Patel, Elsken van der Wall, Paul J van Diest, Venu Raman
PURPOSE: DEAD box protein 3 (DDX3) is an RNA helicase with oncogenic properties that shuttles between the cytoplasm and nucleus. The majority of DDX3 is found in the cytoplasm, but a subset of tumors has distinct nuclear DDX3 localization of yet unknown biological significance. This study aimed to evaluate the significance of and mechanisms behind nuclear DDX3 expression in colorectal and breast cancer. METHODS: Expression of nuclear DDX3 and the nuclear exporter chromosome region maintenance 1 (CRM1) was evaluated by immunohistochemistry in 304 colorectal and 292 breast cancer patient samples...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28760339/crystal-structure-of-importin-%C3%AE-3-bound-to-the-nuclear-localization-signal-of-ran-binding-protein-3
#4
Masako Koyama, Yoshiyuki Matsuura
Ran-binding protein 3 (RanBP3) is a primarily nuclear Ran-binding protein that functions as an accessory factor in the Ran GTPase system. RanBP3 associates with Ran-specific nucleotide exchange factor RCC1 and enhances its catalytic activity towards Ran. RanBP3 also promotes CRM1-mediated nuclear export as well as CRM1-independent nuclear export of β-catenin, Smad2, and Smad3. Nuclear import of RanBP3 is dependent on the nuclear import adaptor protein importin-α and, RanBP3 is imported more efficiently by importin-α3 than by other members of the importin-α family...
September 23, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28753564/exportin-1-xpo1-inhibition-leads-to-restoration-of-tumor-suppressor-mir-145-and-consequent-suppression-of-pancreatic-cancer-cell-proliferation-and-migration
#5
Asfar S Azmi, Yiwei Li, Irfana Muqbil, Amro Aboukameel, William Senapedis, Erkan Baloglu, Yosef Landesman, Sharon Shacham, Michael G Kauffman, Philip A Philip, Ramzi M Mohammad
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer related deaths in the United States with a majority of these patients dying from aggressively invasive and metastatic disease. There is growing evidence that suggests an important role for microRNAs (miRNAs) in the pathobiology of aggressive PDAC. In this study, we found that the expression of miR-145 was significantly lower in PDAC cells when compared to normal pancreatic duct epithelial cells. Here we show that inhibition of the nuclear exporter protein exportin 1 (XPO1; also known as chromosome maintenance region 1 [CRM1]) by siRNA knockdown or by the Selective Inhibitor of Nuclear Export (SINE) compound (KPT-330; selinexor) increases miR-145 expression in PDAC cells resulting in the decreased cell proliferation and migration capacities...
July 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28702009/crm1-inhibitors-for-antiviral-therapy
#6
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
#7
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...
August 15, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28600321/importin-beta-and-crm1-control-a-ranbp2-spatiotemporal-switch-essential-for-mitotic-kinetochore-function
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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...
June 24, 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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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