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https://www.readbyqxmd.com/read/27909249/mortalin-mediated-and-erk-controlled-targeting-of-hif-1%C3%AE-to-mitochondria-confers-resistance-to-apoptosis-under-hypoxia
#1
Ilias Mylonis, Maria Kourti, Martina Samiotaki, George Panayotou, George Simos
Hypoxia inducible factor-1 (HIF-1) is the main transcriptional activator of the cellular response to hypoxia and an important target of anticancer therapy. Phosphorylation by ERK stimulates the transcriptional activity of HIF-1α by inhibiting its CRM1-dependent nuclear export. Here, we demonstrate that phosphorylation by ERK also regulates the association of HIF-1α with a novel interaction partner identified as mortalin (GRP75) which mediates non-genomic involvement of HIF-1α in apoptosis. Mortalin binds specifically to HIF-1α lacking modification by ERK and their complex is localized outside the nucleus...
December 1, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27906185/anti-proliferative-activity-of-the-npm1-interacting-natural-product-avrainvillamide-in-acute-myeloid-leukemia
#2
Vibeke Andresen, Bjarte S Erikstein, Herschel Mukherjee, André Sulen, Mihaela Popa, Steinar Sørnes, Håkon Reikvam, Kok-Ping Chan, Randi Hovland, Emmet McCormack, Øystein Bruserud, Andrew G Myers, Bjørn T Gjertsen
Mutated nucleophosmin 1 (NPM1) acts as a proto-oncogene and is present in ~30% of patients with acute myeloid leukemia (AML). Here we examined the in vitro and in vivo anti-leukemic activity of the NPM1 and chromosome region maintenance 1 homolog (CRM1) interacting natural product avrainvillamide (AVA) and a fully syntetic AVA analog. The NPM1-mutated cell line OCI-AML3 and normal karyotype primary AML cells with NPM1 mutations were significantly more sensitive towards AVA than cells expressing wild-type (wt) NPM1...
December 1, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27903750/nuclear-export-of-ubiquitinated-proteins-determines-the-sensitivity-of-colorectal-cancer-to-proteasome-inhibitor
#3
Tingyu Wu, Wei Chen, Yongwang Zhong, Xiaodan Hou, Shengyun Fang, Chen-Ying Liu, Guanghui Wang, Tong Yu, Yu-Yang Huang, Xuesong Ouyang, Henry Q X Li, Long Cui, Yili Yang
Although proteasome inhibitors such as Bortezomib had significant therapeutic effects in multiple myeloma and mantel cell lymphoma, they exhibited minimal clinical activity as a mono-therapy for solid tumors, including colorectal cancer. We found in the present study that proteasome inhibition induced a remarkable nuclear exportation of ubiquitinated proteins. Inhibition of CRM1, the nuclear export carrier protein, hampered protein export and synergistically enhanced the cytotoxic action of Bortezomib on colon cancer cells containing wild type p53, which underwent G2/M cell cycle block and apoptosis...
November 30, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27902702/selective-inhibitor-of-nuclear-export-sine-compounds-alter-new-world-alphavirus-capsid-localization-and-reduce-viral-replication-in-mammalian-cells
#4
Lindsay Lundberg, Chelsea Pinkham, Cynthia de la Fuente, Ashwini Brahms, Nazly Shafagati, Kylie M Wagstaff, David A Jans, Sharon Tamir, Kylene Kehn-Hall
The capsid structural protein of the New World alphavirus, Venezuelan equine encephalitis virus (VEEV), interacts with the host nuclear transport proteins importin α/β1 and CRM1. Novel selective inhibitor of nuclear export (SINE) compounds, KPT-185, KPT-335 (verdinexor), and KPT-350, target the host's primary nuclear export protein, CRM1, in a manner similar to the archetypical inhibitor Leptomycin B. One major limitation of Leptomycin B is its irreversible binding to CRM1; which SINE compounds alleviate because they are slowly reversible...
November 2016: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/27864780/inhibition-of-the-nuclear-export-of-p65-and-iqcg-in-leukemogenesis-by-nup98-iqcg
#5
Mengmeng Pan, Qiyao Zhang, Ping Liu, Jinyan Huang, Yueying Wang, Saijuan Chen
NUP98 fuses with approximately 34 different partner genes via translocation in hematological malignancies. Transgenic or retrovirus-mediated bone marrow transplanted mouse models reveal the leukemogenesis of some NUP98-related fusion genes. We previously reported the fusion protein NUP98-IQ motif containing G (IQCG) in a myeloid/T lymphoid bi-phenoleukemia patient with t(3;11) and confirmed its leukemogenic ability. Herein, we demonstrated the association of NUP98-IQCG with CRM1, and found that NUP98-IQCG expression inhibits the CRM1-mediated nuclear export of p65 and enhances the transcriptional activity of nuclear factor-κB...
November 18, 2016: Frontiers of Medicine
https://www.readbyqxmd.com/read/27863053/caffeic-acid-phenethyl-ester-cape-revisited-covalent-modulation-of-xpo1-crm1-activities-and-implication-for-its-mechanism-of-action
#6
Sijin Wu, Keren Zhang, Hongqiang Qin, Mingshan Niu, Weijie Zhao, Mingliang Ye, Hanfa Zou, Yongliang Yang
Caffeic acid phenethyl ester (CAPE) is the bioactive constituent of propolis from honeybee hives and is well known for its anti-inflammatory, anti-carcinogenic, antioxidant and immunomodulatory properties. Herein, we revisited the cellular mechanism underlying the diverse biological effects of CAPE. We demonstrated that XPO1/CRM1, a major nuclear export receptor, is a cellular target of CAPE. Through nuclear export functional assay, we observed a clear shift of XPO1 cargo proteins from a cytoplasmic localization to nucleus when treated with CAPE...
November 8, 2016: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/27862840/differential-nucleocytoplasmic-shuttling-of-the-nucleoprotein-of-influenza-a-viruses-and-association-with-host-tropism
#7
Jing Li, Weinan Zheng, Lidan Hou, Can Chen, Wenhui Fan, Hongren Qu, Jingwen Jiang, Jinhua Liu, George F Gao, Jiyong Zhou, Lei Sun, Wenjun Liu
The nucleoprotein (NP) of influenza A virus plays a crucial role in virus replication, infectivity, and host adaptation. As a major component of the viral ribonucleoprotein complexes (vRNP), NP initiates vRNP shuttling between the nucleus and cytoplasm in the host cell. However, the characteristics of the nucleocytoplasmic shuttling of NP from H1N1 influenza A virus still remain unclear. In the present study, the subcellular localization and the related key residues of the H1N1 influenza virus NP were identified and evaluated...
November 8, 2016: Cellular Microbiology
https://www.readbyqxmd.com/read/27852860/nes-masking-regulates-hiv-1-rev-trafficking-and-viral-rna-nuclear-export
#8
Ryan T Behrens, Mounavya Aligeti, Ginger M Pocock, Christina A Higgins, Nathan M Sherer
: HIV-1's Rev protein forms a homooligomeric adaptor complex linking viral RNAs to the cellular CRM1/Ran-GTP nuclear export machinery through the activity of Rev's prototypical leucine-rich nuclear export signal (NES). In this study we used a functional fluorescently-tagged Rev fusion protein as a platform to study the effects of modulating Rev NES identity, number, position, or strength on Rev subcellular trafficking, viral RNA nuclear export, and infectious virion production. We found Rev activity to be remarkably tolerant of diverse NES sequences including supraphysiological NES (SNES) peptides that otherwise arrest CRM1 transport complexes at nuclear pores...
November 16, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27825468/novel-therapeutic-targets-in-waldenstrom-macroglobulinemia
#9
REVIEW
Aneel Paulus, Sikander Ailawadhi, Asher Chanan-Khan
Understanding of molecular mechanisms that drive Waldenstrom macroglobulinemia (WM) cell survival are rapidly evolving. This review briefly highlights emerging "WM-relevant" targets; for which therapeutic strategies are currently being investigated in preclinical and clinical studies. With the discovery of MYD88L265P signaling and remarkable activity of ibrutinib in WM, other targets within the B-cell receptor pathway are now being focused on for therapeutic intervention. Additional targets which play a role in WM cell survival include TLR7, 8 and 9, proteasome-associated deubiquitinating enzymes (USP14 and UCHL5), XPO1/CRM1 and AURKA...
June 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27807029/cellular-nuclear-export-factors-tap-and-aly-are-required-for-hdag-l-mediated-assembly-of-hepatitis-delta-virus
#10
Hsiu-Chen Huang, Chung-Pei Lee, Hui-Kang Liu, Ming-Fu Chang, Yu-Heng Lai, Yu-Ching Lee, Cheng Huang
Hepatitis delta virus (HDV) is a satellite virus of hepatitis B virus (HBV). HDV genome encodes two forms of hepatitis delta antigen (HDAg), small HDAg (HDAg-S), which is required for viral replication, and large HDAg (HDAg-L), which is essential for viral assembly. HDAg-L is identical to HDAg-S except that it bears a 19 amino acid extension at the C terminus. Both HDAgs contain a nuclear localization signal (NLS), but only HDAg-L contains a CRM1-independent nuclear export signal at its C terminus. The nuclear export activity of HDAg-L is important for HDV particle formation...
November 2, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27802336/autographa-californica-multiple-nucleopolyhedrovirus-ac34-protein-retains-cellular-actin-related-protein-2-3-complex-in-the-nucleus-by-subversion-of-crm1-dependent-nuclear-export
#11
Jingfang Mu, Yongli Zhang, Yangyang Hu, Xue Hu, Yuan Zhou, He Zhao, Rongjuan Pei, Chunchen Wu, Jizheng Chen, Han Zhao, Kai Yang, Monique M van Oers, Xinwen Chen, Yun Wang
Actin, nucleation-promoting factors (NPFs), and the actin-related protein 2/3 complex (Arp2/3) are key elements of the cellular actin polymerization machinery. With nuclear actin polymerization implicated in ever-expanding biological processes and the discovery of the nuclear import mechanisms of actin and NPFs, determining Arp2/3 nucleo-cytoplasmic shuttling mechanism is important for understanding the function of nuclear actin. A unique feature of alphabaculovirus infection of insect cells is the robust nuclear accumulation of Arp2/3, which induces actin polymerization in the nucleus to assist in virus replication...
November 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27802322/the-selenocysteine-specific-elongation-factor-contains-unique-sequences-that-are-required-for-both-nuclear-export-and-selenocysteine-incorporation
#12
Aditi Dubey, Paul R Copeland
Selenocysteine (Sec) is a critical residue in at least 25 human proteins that are essential for antioxidant defense and redox signaling in cells. Sec is inserted into proteins cotranslationally by the recoding of an in-frame UGA termination codon to a Sec codon. In eukaryotes, this recoding event requires several specialized factors, including a dedicated, Sec-specific elongation factor called eEFSec, which binds Sec-tRNASec with high specificity and delivers it to the ribosome for selenoprotein production...
2016: PloS One
https://www.readbyqxmd.com/read/27787889/dual-roles-of-the-n-terminal-coiled-coil-domain-of-an-aplysia-sec7-protein-homodimer-formation-and-nuclear-export
#13
Yong-Woo Jun, Seung-Hee Lee, Jaehoon Shim, Jin-A Lee, Chae-Seok Lim, Bong-Kiun Kaang, Deok-Jin Jang
Cytohesin family proteins act as guanine nucleotide exchange factors (GEFs) for the ADP-ribosylation factor (ARF) family of small GTP-binding proteins. Aplysia Sec7 (ApSec7), a member of the cytohesin family in Aplysia, plays key roles in neurite outgrowth in Aplysia neurons. Although ApSec7 has a conserved coiled-coil (CC) domain, its role was not clear. In this study, we found that the CC domain of ApSec7 and ARNO/cytohesin-2 are involved in homodimer formation, leading to efficient plasma membrane targeting of ApSec7 and ARNO/cytohesin-2 in HEK293T cells...
October 27, 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27733172/crm1-xpo1-is-associated-with-clinical-outcome-in-glioma-and-represents-a-therapeutic-target-by-perturbing-multiple-core-pathways
#14
Xuejiao Liu, Yulong Chong, Yiming Tu, Ning Liu, Chenglong Yue, Zhenglei Qi, Huize Liu, Yao Yao, Hongmei Liu, Shangfeng Gao, Mingshan Niu, Rutong Yu
BACKGROUND: Malignant gliomas are associated with a high mortality rate, and effective treatment options are limited. Thus, the development of novel targeted treatments to battle this deadly disease is imperative. METHODS: In this study, we investigated the in vitro effects of the novel reversible chromosomal region maintenance 1 (CRM1) inhibitor S109 on cell proliferation in human gliomas. S109 was also evaluated in an intracranial glioblastoma xenograft model...
October 12, 2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27721408/cytoplasmic-gper-translocation-in-cancer-associated-fibroblasts-mediates-camp-pka-creb-glycolytic-axis-to-confer-tumor-cells-with-multidrug-resistance
#15
T Yu, G Yang, Y Hou, X Tang, C Wu, X-A Wu, L Guo, Q Zhu, H Luo, Y-E Du, S Wen, L Xu, J Yin, G Tu, M Liu
Multiple drug resistance is a challenging issue in the clinic. There is growing evidence that the G-protein-coupled estrogen receptor (GPER) is a novel mediator in the development of multidrug resistance in both estrogen receptor (ER)-positive and -negative breast cancers, and that cancer-associated fibroblasts (CAFs) in the tumor microenvironment may be a new agent that promotes drug resistance in tumor cells. However, the role of cytoplasmic GPER of CAFs on tumor therapy remains unclear. Here we first show that the breast tumor cell-activated PI3K/AKT (phosphoinositide 3-kinase/AKT) signaling pathway induces the cytoplasmic GPER translocation of CAFs in a CRM1-dependent pattern, and leads to the activation of a novel estrogen/GPER/cAMP/PKA/CREB signaling axis that triggers the aerobic glycolysis switch in CAFs...
October 10, 2016: Oncogene
https://www.readbyqxmd.com/read/27714846/both-high-expression-of-nucleophosmin-b23-and-crm1-predicts-poorer-prognosis-in-human-gastric-cancer
#16
Fang Zhou, Ercheng Chen, Dong You, Yipeng Song, Zhenni Sun, Lu Yue
Nucleophosmin/B23 and CRM1 are molecular markers which play an important role in tumorigenesis and tumor progression in gastric cancer (GC). However, the association between the two remains unclear. This study evaluated the expression and the correlation of B23 and CRM1 in GC. B23 and CRM1 expression in GC and adjacent noncancerous tissues (ANCT) of gastrectomy specimens from 131 GC patients was measured by immunohistochemistry. Positive expression rates of B23 and CRM1 were significantly higher in GC tissues than in ANCT...
October 6, 2016: APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica
https://www.readbyqxmd.com/read/27713151/selinexor-a-selective-inhibitor-of-nuclear-export-sine-compound-acts-through-nf-%C3%AE%C2%BAb-deactivation-and-combines-with-proteasome-inhibitors-to-synergistically-induce-tumor-cell-death
#17
Trinayan Kashyap, Christian Argueta, Amro Aboukameel, Thaddeus John Unger, Boris Klebanov, Ramzi M Mohammad, Irfana Muqbil, Asfar S Azmi, Claire Drolen, William Senapedis, Margaret Lee, Michael Kauffman, Sharon Shacham, Yosef Landesman
The nuclear export protein, exportin-1 (XPO1/CRM1), is overexpressed in many cancers and correlates with poor prognosis. Selinexor, a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound, binds covalently to XPO1 and blocks its function. Treatment of cancer cells with selinexor results in nuclear retention of major tumor suppressor proteins and cell cycle regulators, leading to growth arrest and apoptosis. Recently, we described the selection of SINE compound resistant cells and reported elevated expression of inflammation-related genes in these cells...
October 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27697862/human-pdcd2l-is-an-export-substrate-of-crm1-that-associates-with-40s-ribosomal-subunit-precursors
#18
Anne-Marie Landry-Voyer, Sarah Bilodeau, Danny Bergeron, Kiersten L Dionne, Sarah A Port, Caroline Rouleau, François-Michel Boisvert, Ralph H Kehlenbach, François Bachand
The protein arginine methyltransferase 3 (PRMT3) forms a stable complex with the 40S ribosomal protein S2 (RPS2) and contributes to ribosome biogenesis. However, the molecular mechanism by which PRMT3 influences ribosome biogenesis and/or function still remains unclear. Using quantitative proteomics, we identified the human Programmed Cell Death 2-like (PDCD2L) as a novel PRMT3-associated protein. Our data suggest that RPS2 promotes the formation of a conserved extra-ribosomal complex with PRMT3 and PDCD2L...
October 3, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27693556/anti-tumor-activity-of-selective-inhibitor-of-nuclear-export-sine-compounds-is-enhanced-in-non-hodgkin-lymphoma-through-combination-with-mtor-inhibitor-and-dexamethasone
#19
Irfana Muqbil, Amro Aboukameel, Sivan Elloul, Robert Carlson, William Senapedis, Erkan Baloglu, Michael Kauffman, Sharon Shacham, Divaya Bhutani, Jeffrey Zonder, Asfar S Azmi, Ramzi M Mohammad
In previous studies we demonstrated that targeting the nuclear exporter protein exportin-1 (CRM1/XPO1) by a selective inhibitor of nuclear export (SINE) compound is a viable therapeutic strategy against Non-Hodgkin Lymphoma (NHL). Our studies along with pre-clinical work from others led to the evaluation of the lead SINE compound, selinexor, in a phase 1 trial in patients with CLL or NHL (NCT02303392). Continuing our previous work, we studied combinations of selinexor-dexamethasone (DEX) and selinexor-everolimus (EVER) in NHL...
September 28, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27680702/xpo1-dependent-nuclear-export-is-a-druggable-vulnerability-in-kras-mutant-lung-cancer
#20
Jimi Kim, Elizabeth McMillan, Hyun Seok Kim, Niranjan Venkateswaran, Gurbani Makkar, Jaime Rodriguez-Canales, Pamela Villalobos, Jasper Edgar Neggers, Saurabh Mendiratta, Shuguang Wei, Yosef Landesman, William Senapedis, Erkan Baloglu, Chi-Wan B Chow, Robin E Frink, Boning Gao, Michael Roth, John D Minna, Dirk Daelemans, Ignacio I Wistuba, Bruce A Posner, Pier Paolo Scaglioni, Michael A White
The common participation of oncogenic KRAS proteins in many of the most lethal human cancers, together with the ease of detecting somatic KRAS mutant alleles in patient samples, has spurred persistent and intensive efforts to develop drugs that inhibit KRAS activity. However, advances have been hindered by the pervasive inter- and intra-lineage diversity in the targetable mechanisms that underlie KRAS-driven cancers, limited pharmacological accessibility of many candidate synthetic-lethal interactions and the swift emergence of unanticipated resistance mechanisms to otherwise effective targeted therapies...
September 28, 2016: Nature
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