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https://www.readbyqxmd.com/read/29321323/hiv-1-vif-s-capacity-to-manipulate-the-cell-cycle-is-species-specific
#1
Edward L Evans, Jordan T Becker, Stephanie L Fricke, Kishan Patel, Nathan M Sherer
Cells derived from mice and other rodents exhibit profound blocks to HIV-1 virion production reflecting species-specific incompatibilities between viral Tat and Rev proteins and essential host factors Cyclin T1 (CCNT1) and Exportin-1 (XPO1, also known as CRM1), respectively. To determine if mouse cell blocks other than CCNT1 and XPO1 affect HIV's post-integration stages, we studied HIV-1NL4-3 gene expression in mouse NIH 3T3 cells modified to constitutively express HIV-1 compatible versions of CCNT1 and XPO1 (3T3...
January 10, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29304833/a-phase-i-study-of-selinexor-in-combination-with-high-dose-cytarabine-and-mitoxantrone-for-remission-induction-in-patients-with-acute-myeloid-leukemia
#2
Amy Y Wang, Howard Weiner, Margaret Green, Hua Chang, Noreen Fulton, Richard A Larson, Olatoyosi Odenike, Andrew S Artz, Michael R Bishop, Lucy A Godley, Michael J Thirman, Satyajit Kosuri, Jane E Churpek, Emily Curran, Kristen Pettit, Wendy Stock, Hongtao Liu
BACKGROUND: Novel therapies for patients with acute myeloid leukemia (AML) are imperative, particularly for those with high-risk features. Selinexor, an exportin 1 (XPO1/CRM1) inhibitor, has demonstrated anti-leukemia activity as a single agent, as well as in combination with anthracyclines and/or DNA-damaging agents. METHODS: We report the findings of a phase I dose escalation trial with cohort expansion in 20 patients with newly diagnosed or relapsed/refractory AML that combined selinexor with age-adjusted high-dose cytarabine and mitoxantrone (HiDAC/Mito)...
January 5, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29247643/traditional-herbal-medicine-derived-sulforaphene-promotes-mitophagic-cell-death-in-lymphoma-cells-through-crm1-mediated-p62-sqstm1-accumulation-and-ampk-activation
#3
Haina Wang, Fuqiang Wang, Sijin Wu, Zhiheng Liu, Tingting Li, Lei Mao, Jie Zhang, Cheng Li, Caigang Liu, Yongliang Yang
Sulforaphene (LFS-01) is the major chemical constituent of Raphanus sativus, a medicinal herb used for over a thousand years in traditional Chinese medicine. Here we identified that LFS-01 can selectively eradicate lymphoma cells while sparing normal lymphocytes by triggering concomitant mitophagy and apoptosis. We demonstrated that LFS-01 can retain Nrf2 in the nucleus by covalently modulating CRM1 and consequently upregulate p62/SQSTM1, an essential structural component of the autophagosomes during mitophagic process...
December 13, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/29175376/control-of-nuclear-%C3%AE-dystroglycan-content-is-crucial-for-the-maintenance-of-nuclear-envelope-integrity-and-function
#4
Griselda Vélez-Aguilera, Juan de Dios Gómez-López, Guadalupe E Jiménez-Gutiérrez, Alejandra Vásquez-Limeta, Marco S Laredo-Cisneros, Pablo Gómez, Steve J Winder, Bulmaro Cisneros
β-dystroglycan (β-DG) is a plasma membrane protein that has ability to target to the nuclear envelope (NE) to maintain nuclear architecture. Nevertheless, mechanisms controlling β-DG nuclear localization and the physiological consequences of a failure of trafficking are largely unknown. We show that β-DG has a nuclear export pathway in myoblasts that depends on the recognition of a nuclear export signal located in its transmembrane domain, by CRM1. Remarkably, NES mutations forced β-DG nuclear accumulation resulting in mislocalization and decreased levels of emerin and lamin B1 and disruption of various nuclear processes in which emerin (centrosome-nucleus linkage and β-catenin transcriptional activity) and lamin B1 (cell cycle progression and nucleoli structure) are critically involved...
November 21, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29155058/foxo-1-contributes-to-the-efficacy-of-the-combination-of-the-xpo1-inhibitor-selinexor-and-cisplatin-in-ovarian-carcinoma-preclinical-models
#5
Cristina Corno, Simone Stucchi, Michelandrea De Cesare, Nives Carenini, Serena Stamatakos, Emilio Ciusani, Lucia Minoli, Eugenio Scanziani, Christian Argueta, Yosef Landesman, Nadia Zaffaroni, Laura Gatti, Paola Perego
The XPO1/CRM1 inhibitor selinexor (KPT-330), is currently being evaluated in multiple clinical trials as an anticancer agent. XPO1 participates in the nuclear export of FoxO-1, which we previously found to be decreased in platinum-resistant ovarian carcinoma. The aim of this study was to determine whether enriching FoxO-1 nuclear localization using selinexor would increase ovarian cancer cell sensitivity to cisplatin. Selinexor, as a single agent, displayed a striking antiproliferative effect in different ovarian carcinoma cell lines...
November 16, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29137251/exportin-1-xpo1-inhibition-leads-to-restoration-of-tumor-suppressor-mir-145-and-consequent-suppression-of-pancreatic-cancer-cell-proliferation-and-migration
#6
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...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29101390/l290p-v-mutations-increase-erk3-s-cytoplasmic-localization-and-migration-invasion-promoting-capability-in-cancer-cells
#7
Hadel Alsaran, Lobna Elkhadragy, Astha Shakya, Weiwen Long
Protein kinases are frequently mutated in human cancers, which leads to altered signaling pathways and contributes to tumor growth and progression. ERK3 is an atypical mitogen-activated protein kinase (MAPK) containing an S-E-G activation motif rather than the conserved T-X-Y motif in conventional MAPKs such as ERK1/2. Recent studies have revealed important roles for ERK3 in cancers. ERK3 promotes cancer cell migration/invasion and tumor metastasis, and its expression is upregulated in multiple cancers. Little is known, however, regarding ERK3 mutations in cancers...
November 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29053568/mutation-of-a-conserved-nuclear-export-sequence-in-chikungunya-virus-capsid-protein-disrupts-host-cell-nuclear-import
#8
Susan C Jacobs, Adam Taylor, Lara J Herrero, Suresh Mahalingam, John K Fazakerley
Transmitted by mosquitoes; chikungunya virus (CHIKV) is responsible for frequent outbreaks of arthritic disease in humans. CHIKV is an arthritogenic alphavirus of the Togaviridae family. Capsid protein, a structural protein encoded by the CHIKV RNA genome, is able to translocate to the host cell nucleus. In encephalitic alphaviruses nuclear translocation induces host cell shut off; however, the role of capsid protein nuclear localisation in arthritogenic alphaviruses remains unclear. Using replicon systems, we investigated a nuclear export sequence (NES) in the N-terminal region of capsid protein; analogous to that found in encephalitic alphavirus capsid but uncharacterised in CHIKV...
October 20, 2017: Viruses
https://www.readbyqxmd.com/read/29028476/differential-interaction-between-human-and-murine-crm1-and-lentiviral-rev-proteins
#9
Yan Yue, Ayse K Coskun, Navneet Jawanda, Jim Auer, Richard E Sutton
Mice have multiple obstacles to HIV replication, including a block of unspliced and partially spliced viral mRNA nuclear export. In human, Rev binds to the Rev-response element and human (h) Crm1, facilitating nuclear export of RRE-containing viral RNAs. Murine (m) Crm1 is less functional than hCrm1 in this regard. Here we demonstrated that in biochemical experiments mCrm1 failed to interact with HIV Rev whereas hCrm1 did. In genetic experiments in human cells, we observed a modest but significant differential effect between mCrm1 and hCrm1, which was also true of other lentiviral Revs tested...
October 10, 2017: Virology
https://www.readbyqxmd.com/read/28992066/tfiia-transcriptional-activity-is-controlled-by-a-cleave-and-run-exportin-1-taspase-1-switch
#10
Christian Schrenk, Verena Fetz, Cecilia Vallet, Christina Heiselmayer, Elisabeth Schröder, Astrid Hensel, Angelina Hahlbrock, Désirée Wünsch, Dorothee Goesswein, Carolin Bier, Negusse Habtemichael, Günter Schneider, Roland H Stauber, Shirley K Knauer
Transcription factor TFIIA is controlled by complex regulatory networks including proteolysis by the protease Taspase 1, though the full impact of cleavage remains elusive. Here, we demonstrate that in contrast to the general assumption, de novo produced TFIIA is rapidly confined to the cytoplasm via an evolutionary conserved nuclear export signal (NES, amino acids 21VINDVRDIFL30), interacting with the nuclear export receptor Exportin-1/chromosomal region maintenance 1 (Crm1). Chemical export inhibition or genetic inactivation of the NES not only promotes TFIIA's nuclear localization but also affects its transcriptional activity...
August 10, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/28981101/reciprocal-amplification-of-caspase-3-activity-by-nuclear-export-of-a-putative-human-rna-modifying-protein-pus10-during-trail-induced-apoptosis
#11
Sujata Jana, Andrew C Hsieh, Ramesh Gupta
Pus10 is a pseudouridine synthase present in Archaea and Eukarya, but not in Bacteria and yeast. It has been suggested that the human PUS10 (DOBI) gene is needed during TRAIL-induced apoptosis. We analyzed the role of PUS10 in TRAIL-induced apoptosis by immunofluorescence, immunoblotting and several indicators of apoptosis. We examined several TRAIL-sensitive cell lines and we also examined some resistant cell lines after treatment with cycloheximide. PUS10 is mainly present in the nucleus. Early during apoptosis, PUS10 translocates to mitochondria via CRM1-mediated export with the concurrent release of cytochrome c and SMAC...
October 5, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28974580/sumoylation-regulates-nuclear-accumulation-and-signaling-activity-of-the-soluble-intracellular-domain-of-the-erbb4-receptor-tyrosine-kinase
#12
Anna Maria Knittle, Maria Helkkula, Mark S Johnson, Maria Sundvall, Klaus Elenius
Erb-B2 receptor tyrosine kinase 4 (ErbB4) is a kinase that can signal via a proteolytically released intracellular domain (ICD) in addition to classical receptor tyrosine kinase-activated signaling cascades. Previously, we have demonstrated that ErbB4 ICD is posttranslationally modified by the small ubiquitin-like modifier (SUMO) and functionally interacts with the PIAS3 SUMO E3 ligase. However, direct evidence of SUMO modification in ErbB4 signaling has remained elusive. Here, we report that the conserved lysine residue 714 in the ErbB4 ICD undergoes SUMO modification, which was reversed by sentrin-specific proteases (SENPs) 1, 2 and 5...
October 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28961161/venezuelan-equine-encephalitis-virus-capsid-the-clever-caper
#13
REVIEW
Lindsay Lundberg, Brian Carey, Kylene Kehn-Hall
Venezuelan equine encephalitis virus (VEEV) is a New World alphavirus that is vectored by mosquitos and cycled in rodents. It can cause disease in equines and humans characterized by a febrile illness that may progress into encephalitis. Like the capsid protein of other viruses, VEEV capsid is an abundant structural protein that binds to the viral RNA and interacts with the membrane-bound glycoproteins. It also has protease activity, allowing cleavage of itself from the growing structural polypeptide during translation...
September 29, 2017: Viruses
https://www.readbyqxmd.com/read/28942004/leptomycin-b-reduces-primary-and-acquired-resistance-of-gefitinib-in-lung-cancer-cells
#14
Zhongwei Liu, Weimin Gao
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib has demonstrated dramatic clinical efficacy in non-small cell lung cancer (NSCLC) patients. However, its therapeutic efficacy is ultimately limited by the development of acquired drug resistance. The aim of this study was to explore the potential utility of chromosome region maintenance 1 (CRM1) inhibitor leptomycin B (LMB) in combination with gefitinib to overcome primary and acquired gefitinib resistance in NSCLC cells. The combinative effects of gefitinib and LMB were evaluated by MTT and its underlining mechanism was assessed by flow cytometry and Western blot...
November 15, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28830558/identification-of-a-homogenous-structural-basis-for-oligomerization-by-retroviral-rev-like-proteins
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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