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https://www.readbyqxmd.com/read/29775781/phosphorylation-and-dephosphorylation-of-threonine-188-in-nucleoprotein-is-crucial-for-the-replication-of-influenza-a-virus
#1
Yun Li, Lei Sun, Weinan Zheng, Madina Mahesutihan, Jing Li, Yuhai Bi, Heran Wang, Wenjun Liu, Ting Rong Luo
Nucleoprotein (NP) is a major component of the viral ribonucleoprotein (vRNP) complex that is responsible for viral replication, transcription and packaging of influenza A virus. Phosphorylation of NP plays an important role during viral infection. In the present study, we identified threonine 188 (T188) as a novel phosphorylated residue in the NP of influenza A virus by using mass spectrometry. T188 is located within nuclear export signal 2 (NES2) which is chromosome region maintenance 1 (CRM1)-independent...
May 15, 2018: Virology
https://www.readbyqxmd.com/read/29765539/crm1-xpo1-expression-in-pancreatic-adenocarcinoma-correlates-with-survivin-expression-and-the-proliferative-activity
#2
David M Saulino, Pamela S Younes, Jennifer M Bailey, Mamoun Younes
CRM1/XPO1 (CRM1) is a nuclear export chaperone that mediates the export of proteins essential to growth regulation and tumor suppression. Its overexpression in tumors was found to be associated with poor prognosis. Selective inhibitors of nuclear export are in phase I and II clinical trials for several tumor types. Our aim was to investigate CRM1 expression in pancreatic adenocarcinoma (PAC) and its relationship to survivin expression and the proliferative activity. Sections of tissue microarray containing 76 formalin fixed and paraffin embedded PAC were stained by immunohistochemistry (IHC) for CRM1, survivin, and Cyclin A...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29748336/xpo7-is-a-broad-spectrum-exportin-and-a-nuclear-import-receptor
#3
Metin Aksu, Tino Pleiner, Samir Karaca, Christin Kappert, Heinz-Jürgen Dehne, Katharina Seibel, Henning Urlaub, Markus T Bohnsack, Dirk Görlich
Exportins bind cargo molecules in a RanGTP-dependent manner inside nuclei and transport them through nuclear pores to the cytoplasm. CRM1/Xpo1 is the best-characterized exportin because specific inhibitors such as leptomycin B allow straightforward cargo validations in vivo. The analysis of other exportins lagged far behind, foremost because no such inhibitors had been available for them. In this study, we explored the cargo spectrum of exportin 7/Xpo7 in depth and identified not only ∼200 potential export cargoes but also, surprisingly, ∼30 nuclear import substrates...
May 10, 2018: Journal of Cell Biology
https://www.readbyqxmd.com/read/29735942/nuclear-export-inhibition-for-pancreatic-cancer-therapy
#4
REVIEW
Irfana Muqbil, Asfar S Azmi, Ramzi M Mohammad
Pancreatic cancer is a deadly disease that is resistant to most available therapeutics. Pancreatic cancer to date has no effective drugs that could enhance the survival of patients once their disease has metastasized. There is a need for the identification of novel actionable drug targets in this unusually recalcitrant cancer. Nuclear protein transport is an important mechanism that regulates the function of several tumor suppressor proteins (TSPs) in a compartmentalization-dependent manner. High expression of the nuclear exporter chromosome maintenance region 1 (CRM1) or exportin 1 (XPO1), a common feature of several cancers including pancreatic cancer, results in excessive export of critical TSPs to the incorrect cellular compartment, leading to their functional inactivation...
May 7, 2018: Cancers
https://www.readbyqxmd.com/read/29728564/nuclear-egress-of-tdp-43-and-fus-occurs-independently-of-exportin-1-crm1
#5
Helena Ederle, Christina Funk, Claudia Abou-Ajram, Saskia Hutten, Eva B E Funk, Ralph H Kehlenbach, Susanne M Bailer, Dorothee Dormann
TDP-43 and FUS are nuclear proteins with multiple functions in mRNA processing. They play key roles in ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia), where they are partially lost from the nucleus and aggregate in the cytoplasm of neurons and glial cells. Defects in nucleocytoplasmic transport contribute to this pathology, hence nuclear import of both proteins has been studied in detail. However, their nuclear export routes remain poorly characterized and it is unclear whether aberrant nuclear export contributes to TDP-43 or FUS pathology...
May 4, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29725458/crm1-a-novel-independent-prognostic-factor-overexpressed-in-invasive-breast-carcinoma-of-poor-prognosis
#6
Lu Yue, Zhen-Ni Sun, Ya-Sai Yao, Zan Shen, Hai-Bo Wang, Xiang-Ping Liu, Fang Zhou, Jin-Yu Xiang, Ru-Yong Yao, Hai-Tao Niu
Breast cancer (BC) is the most commonly diagnosed cancer in females globally and is more aggressive at later stages. Chromosome region maintenance 1 (CRM1) is involved in the nuclear export of proteins and RNAs and has been associated with a number of malignancies. However, the clinicopathological significance of its expression in BC remains to be elucidated therefore this was investigated in the present study. CRM1 expression in 280 breast cancer tissues and 60 normal tissues was retrospectively analyzed using immunohistochemistry (IHC) and western blotting...
May 2018: Oncology Letters
https://www.readbyqxmd.com/read/29707241/kpt-330-inhibition-of-chromosome-region-maintenance-1-is-cytotoxic-and-sensitizes-chronic-myeloid-leukemia-to-imatinib
#7
Danian Nie, Kezhi Huang, Songmei Yin, Yiqing Li, Shuangfeng Xie, Liping Ma, Xiuju Wang, Yudan Wu, Jie Xiao, Jieyu Wang, Wenjuan Yang, Hongyun Liu
As tyrosine kinase inhibitors (e.g., Imatinib, IM) fail to induce long-term response in some chronic myeloid leukemia (CML), novel therapies targeting leukemia-dysregulated pathways are necessary. Nuclear-cytoplasmic trafficking of proteins play a key role in the development of leukemia and drug resistance. KPT-330 (Selinexor), an inhibitor of chromosome region maintenance 1 (CRM1, nuclear receptor exportin 1, XPO1), demonstrated activities against a few hematological malignancies. We examined the anti-leukemic efficacy of KPT-330 in IM-resistant CML...
2018: Cell Death Discovery
https://www.readbyqxmd.com/read/29666234/nuclear-export-of-ubiquitinated-proteins-via-the-ubin-post-system
#8
Shoshiro Hirayama, Munechika Sugihara, Daisuke Morito, Shun-Ichiro Iemura, Tohru Natsume, Shigeo Murata, Kazuhiro Nagata
Although mechanisms for protein homeostasis in the cytosol have been studied extensively, those in the nucleus remain largely unknown. Here, we identified that a protein complex mediates export of polyubiquitinated proteins from the nucleus to the cytosol. UBIN, a ubiquitin-associated (UBA) domain-containing protein, shuttled between the nucleus and the cytosol in a CRM1-dependent manner, despite the lack of intrinsic nuclear export signal (NES). Instead, the UBIN binding protein polyubiquitinated substrate transporter (POST) harboring an NES shuttled UBIN through nuclear pores...
April 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29666159/extensive-identification-and-in-depth-validation-of-importin-13-cargoes
#9
Imke Baade, Christiane Spillner, Kerstin Schmitt, Oliver Valerius, Ralph H Kehlenbach
Importin 13 is a member of the importin b family of transport receptors. Unlike most family members, importin 13 mediates both, nuclear protein import and export. To search for novel importin 13 cargoes, we used stable isotope labeling of amino acids in cell culture (SILAC) and mass spectrometry. Using stringent criteria, we identified 255 importin 13 substrates, including the known cargoes Ubc9, Mago and eIF1A, and validate many of them as transport cargoes by extensive biochemical and cell biological characterization...
April 17, 2018: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/29590630/two-differential-binding-mechanisms-of-fg-nucleoporins-and-nuclear-transport-receptors
#10
Piau Siong Tan, Iker Valle Aramburu, Davide Mercadante, Swati Tyagi, Aritra Chowdhury, Daniel Spitz, Sarah L Shammas, Frauke Gräter, Edward A Lemke
Phenylalanine-glycine-rich nucleoporins (FG-Nups) are intrinsically disordered proteins, constituting the selective barrier of the nuclear pore complex (NPC). Previous studies showed that nuclear transport receptors (NTRs) were found to interact with FG-Nups by forming an "archetypal-fuzzy" complex through the rapid formation and breakage of interactions with many individual FG motifs. Here, we use single-molecule studies combined with atomistic simulations to show that, in sharp contrast, FG-Nup214 undergoes a coupled reconfiguration-binding mechanism when interacting with the export receptor CRM1...
March 27, 2018: Cell Reports
https://www.readbyqxmd.com/read/29482494/nologo-a-new-statistical-model-highlights-the-diversity-and-suggests-new-classes-of-crm1-dependent-nuclear-export-signals
#11
Muluye E Liku, Elizabeth-Ann Legere, Alan M Moses
BACKGROUND: Crm1-dependent Nuclear Export Signals (NESs) are clusters of alternating hydrophobic and non-hydrophobic amino acid residues between 10 to 15 amino acids in length. NESs were largely thought to follow simple consensus patterns, based on which they were categorized into 6-10 classes. However, newly discovered NESs often deviate from the established consensus patterns. Thus, identifying NESs within protein sequences remains a bioinformatics challenge. RESULTS: We describe a probabilistic representation of NESs using a new generative model we call NoLogo that can account for a large diversity of NESs...
February 27, 2018: BMC Bioinformatics
https://www.readbyqxmd.com/read/29476013/karyopherin-%C3%AE-3-is-a-key-protein-in-the-pathogenesis-of-spinocerebellar-ataxia-type-3-controlling-the-nuclear-localization-of-ataxin-3
#12
Anna Sergeevna Sowa, Elodie Martin, Inês Morgado Martins, Jana Schmidt, Reinhard Depping, Jonasz Jeremiasz Weber, Franziska Rother, Enno Hartmann, Michael Bader, Olaf Riess, Hervé Tricoire, Thorsten Schmidt
Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by a CAG expansion in the ATXN3 gene leading to a polyglutamine expansion in the ataxin-3 protein. The nuclear presence and aggregation of expanded ataxin-3 are critical steps in disease pathogenesis. To identify novel therapeutic targets, we investigated the nucleocytoplasmic transport system by screening a collection of importins and exportins that potentially modulate this nuclear localization. Using cell, Drosophila , and mouse models, we focused on three transport proteins, namely, CRM1, IPO13, KPNA3, and their respective Drosophila orthologs Emb, Cdm, and Kap-α3...
March 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29459360/phosphorylation-of-bach1-switches-its-function-from-transcription-factor-to-mitotic-chromosome-regulator-and-promotes-its-interaction-with-hmmr
#13
Jie Li, Hiroki Shima, Hironari Nishizawa, Masatoshi Ikeda, Andrey Brydun, Mitsuyo Matsumoto, Hiroki Kato, Yuriko Saiki, Liang Liu, Miki Watanabe-Matsui, Kenji Iemura, Kozo Tanaka, Takuma Shiraki, Kazuhiko Igarashi
The transcription repressor BACH1 performs mutually independent dual roles in transcription regulation and chromosome alignment during mitosis by supporting polar ejection force of mitotic spindle. We now found that the mitotic spindles became oblique relative to the adhesion surface following endogenous BACH1 depletion in HeLa cells. This spindle orientation rearrangement was rescued by re-expression of BACH1 depending on its interactions with HMMR and CRM1, both of which are required for the positioning of mitotic spindle, but independently of its DNA-binding activity...
March 15, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29442331/role-of-zic-family-proteins-in-transcriptional-regulation-and-chromatin-remodeling
#14
Minoru Hatayama, Jun Aruga
Proper functions of Zic proteins are essential for animals in health and disease. Here, we summarize our current understanding of the molecular properties and functions of the Zic family across animal species and paralog subtypes. Zics are basic proteins with some posttranslational modifications and can move to the cell nucleus via importin- and CRM1-based nucleocytoplasmic shuttling mechanisms. Degradation is mediated by the ubiquitin proteasome system. Many Zic proteins are capable of binding to two types of target DNA sequences (CTGCTG-core-type and GC-stretch-type)...
2018: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29407444/nuclear-import-and-export-of-the-thyroid-hormone-receptor
#15
Jibo Zhang, Vincent R Roggero, Lizabeth A Allison
The thyroid hormone receptors, TRα1 and TRβ1, are members of the nuclear receptor superfamily that forms one of the most abundant classes of transcription factors in multicellular organisms. Although primarily localized to the nucleus, TRα1 and TRβ1 shuttle rapidly between the nucleus and cytoplasm. The fine balance between nuclear import and export of TRs has emerged as a critical control point for modulating thyroid hormone-responsive gene expression. Mutagenesis studies have defined two nuclear localization signal (NLS) motifs that direct nuclear import of TRα1: NLS-1 in the hinge domain and NLS-2 in the N-terminal A/B domain...
2018: Vitamins and Hormones
https://www.readbyqxmd.com/read/29398448/nucleo-cytosolic-shuttling-of-argonaute1-prompts-a-revised-model-of-the-plant-microrna-pathway
#16
Nicolas G Bologna, Raphael Iselin, Luciano A Abriata, Alexis Sarazin, Nathan Pumplin, Florence Jay, Thomas Grentzinger, Matteo Dal Peraro, Olivier Voinnet
Unlike in metazoans, plant microRNAs (miRNAs) undergo stepwise nuclear maturation before engaging cytosolic, sequence-complementary transcripts in association with the silencing effector protein ARGONAUTE1 (AGO1). Since their discovery, how and under which form plant miRNAs translocate to the cytosol has remained unclear, as has their sub-cellular AGO1 loading site(s). Here, we show that the N termini of all plant AGO1s contain a nuclear-localization (NLS) and nuclear-export signal (NES) that, in Arabidopsis thaliana (At), enables AtAGO1 nucleo-cytosolic shuttling in a Leptomycin-B-inhibited manner, diagnostic of CRM1(EXPO1)/NES-dependent nuclear export...
February 15, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29361733/verdinexor-targeting-of-crm1-is-a-promising-therapeutic-approach-against-rsv-and-influenza-viruses
#17
REVIEW
Jennifer A Pickens, Ralph A Tripp
Two primary causes of respiratory tract infections are respiratory syncytial virus (RSV) and influenza viruses, both of which remain major public health concerns. There are a limited number of antiviral drugs available for the treatment of RSV and influenza, each having limited effectiveness and each driving selective pressure for the emergence of drug-resistant viruses. Novel broad-spectrum antivirals are needed to circumvent problems with current disease intervention strategies, while improving the cytokine-induced immunopathology associated with RSV and influenza infections...
January 21, 2018: Viruses
https://www.readbyqxmd.com/read/29361525/stress-activated-mapks-and-crm1-regulate-the-subcellular-localization-of-net1a-to-control-cell-motility-and-invasion
#18
Arzu Ulu, Wonkyung Oh, Yan Zuo, Jeffrey A Frost
The neuroepithelial cell transforming gene 1A (Net1A, an isoform of Net1) is a RhoA subfamily guanine nucleotide exchange factor (GEF) that localizes to the nucleus in the absence of stimulation, preventing it from activating RhoA. Once relocalized in the cytosol, Net1A stimulates cell motility and extracellular matrix invasion. In the present work, we investigated mechanisms responsible for the cytosolic relocalization of Net1A. We demonstrate that inhibition of MAPK pathways blocks Net1A relocalization, with cells being most sensitive to JNK pathway inhibition...
February 1, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29321323/hiv-1-vif-s-capacity-to-manipulate-the-cell-cycle-is-species-specific
#19
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 postintegration 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...
April 1, 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
#20
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
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