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https://www.readbyqxmd.com/read/29773601/combinatorial-targeting-of-xpo1-and-flt3-exerts-synergistic-anti-leukemia-effects-through-induction-of-differentiation-and-apoptosis-in-flt3-mutated-acute-myeloid-leukemias-from-concept-to-clinical-trial
#1
Weiguo Zhang, Charlie Ly, Jo Ishizawa, Hong Mu, Vivian Ruvolo, Sharon Shacham, Naval Daver, Michael Andreeff
Targeted therapies against FLT3-mutated acute myeloid leukemia have shown limited clinical efficacy primarily because of the acquisition of secondary mutations in FLT3 and persistent activation of downstream pro-survival pathways such as MEK/ERK, PI3K/AKT, and STAT5. Activation of these additional kinases may also result in phosphorylation of tumor suppressor proteins promoting their nuclear export. Thus, co-targeting nuclear export proteins (i.e., XPO1) and FLT3 concomitantly may be therapeutically effective...
May 17, 2018: Haematologica
https://www.readbyqxmd.com/read/29768192/nuclear-export-inhibition-enhances-hlh-30-tfeb-activity-autophagy-and-lifespan
#2
Melissa J Silvestrini, Joseph R Johnson, Anita V Kumar, Tara G Thakurta, Karine Blais, Zachary A Neill, Sarah W Marion, Victoria St Amand, Robert A Reenan, Louis R Lapierre
Transcriptional modulation of the process of autophagy involves the transcription factor HLH-30/TFEB. In order to systematically determine the regulatory network of HLH-30/TFEB, we performed a genome-wide RNAi screen in C. elegans and found that silencing the nuclear export protein XPO-1/XPO1 enhances autophagy by significantly enriching HLH-30 in the nucleus, which is accompanied by proteostatic benefits and improved longevity. Lifespan extension via xpo-1 silencing requires HLH-30 and autophagy, overlapping mechanistically with several established longevity models...
May 15, 2018: Cell Reports
https://www.readbyqxmd.com/read/29765539/crm1-xpo1-expression-in-pancreatic-adenocarcinoma-correlates-with-survivin-expression-and-the-proliferative-activity
#3
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
#4
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/29746670/dicer-cleaves-5-extended-microrna-precursors-originating-from-rna-polymerase-ii-transcription-start-sites
#5
Peike Sheng, Christopher Fields, Kelsey Aadland, Tianqi Wei, Oralia Kolaczkowski, Tongjun Gu, Bryan Kolaczkowski, Mingyi Xie
MicroRNAs (miRNAs) are approximately 22 nucleotide (nt) long and play important roles in post-transcriptional regulation in both plants and animals. In animals, precursor (pre-) miRNAs are ∼70 nt hairpins produced by Drosha cleavage of long primary (pri-) miRNAs in the nucleus. Exportin-5 (XPO5) transports pre-miRNAs into the cytoplasm for Dicer processing. Alternatively, pre-miRNAs containing a 5' 7-methylguanine (m7G-) cap can be generated independently of Drosha and XPO5. Here we identify a class of m7G-capped pre-miRNAs with 5' extensions up to 39 nt long...
May 9, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29735942/nuclear-export-inhibition-for-pancreatic-cancer-therapy
#6
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/29728608/active-nuclear-import-and-passive-nuclear-export-are-the-primary-determinants-of-tdp-43-localization
#7
Emile S Pinarbasi, Tolga Cağatay, Ho Yee Joyce Fung, Ying C Li, Yuh Min Chook, Philip J Thomas
ALS (Amyotrophic Lateral Sclerosis) is a neurodegenerative disease characterized by the redistribution of the RNA binding protein TDP-43 in affected neurons: from predominantly nuclear to aggregated in the cytosol. However, the determinants of TDP-43 localization and the cellular insults that promote redistribution are incompletely understood. Here, we show that the putative Nuclear Export Signal (NES) is not required for nuclear egress of TDP-43. Moreover, when the TDP-43 domain which contains the putative NES is fused to a reporter protein, YFP, the presence of the NES is not sufficient to mediate nuclear exclusion of the fusion protein...
May 4, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29707241/kpt-330-inhibition-of-chromosome-region-maintenance-1-is-cytotoxic-and-sensitizes-chronic-myeloid-leukemia-to-imatinib
#8
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/29650799/pervasive-mutations-of-jak-stat-pathway-genes-in-classical-hodgkin-lymphoma
#9
Enrico Tiacci, Erik Ladewig, Gianluca Schiavoni, Alex Penson, Elisabetta Fortini, Valentina Pettirossi, Yuchun Wang, Ariele Rosseto, Alessandra Venanzi, Sofija Vlasevska, Roberta Pacini, Simonetta Piattoni, Alessia Tabarrini, Alessandra Pucciarini, Barbara Bigerna, Alessia Santi, Alessandro M Gianni, Simonetta Viviani, Antonello Cabras, Stefano Ascani, Barbara Crescenzi, Cristina Mecucci, Laura Pasqualucci, Raul Rabadan, Brunangelo Falini
Dissecting the pathogenesis of classical Hodgkin lymphoma (cHL), a common cancer in young adults, remains challenging due to the rarity of tumor cells in involved tissues (usually <5%). Here, we analyzed the coding genome of cHL by microdissecting tumor and normal cells from 34 patient biopsies, for a total of ~50,000 singly isolated lymphoma cells. We uncovered several recurrently mutated genes, namely STAT6 (32% of cases), GNA13 (24%), XPO1 (18%) and ITPKB (16%), and document the functional role of mutant STAT6 in sustaining tumor cell viability...
April 12, 2018: Blood
https://www.readbyqxmd.com/read/29616892/mapping-the-nuclear-localization-signal-in-the-matrix-protein-of-potato-yellow-dwarf-virus
#10
Gavin Anderson, Chanyong Jang, Renyuan Wang, Michael Goodin
The ability of the matrix (M) protein of potato yellow dwarf virus (PYDV) to remodel nuclear membranes is controlled by a di-leucine motif located at residues 223 and 224 of its primary structure. This function can be uncoupled from that of its nuclear localization signal (NLS), which is controlled primarily by lysine and arginine residues immediately downstream of the LL motif. In planta localization of green fluorescent protein fusions, bimolecular fluorescence complementation assays with nuclear import receptor importin-α1 and yeast-based nuclear import assays provided three independent experimental approaches to validate the authenticity of the M-NLS...
May 2018: Journal of General Virology
https://www.readbyqxmd.com/read/29610030/clinical-implications-of-targeting-xpo1-mediated-nuclear-export-in-multiple-myeloma
#11
REVIEW
Ujjawal H Gandhi, William Senapedis, Erkan Baloglu, Thaddeus J Unger, Ajai Chari, Dan Vogl, Robert F Cornell
Multiple myeloma (MM) is a malignancy of plasma cells that is typically chronic, and relapse is common. Current therapeutic strategies include combination and sequential treatments with corticosteroids, alkylating agents, proteasomal inhibitors, immunomodulators, and monoclonal antibodies. These drugs prolong survival but ultimately become ineffective. Exportin 1 (XPO1), a nuclear export protein, is overexpressed in MM cells, and knockdown studies have suggested that XPO1 is essential for MM cell survival. Selective inhibitor of nuclear export (SINE) compounds are novel, orally bioavailable class of agents that specifically inhibit XPO1...
March 14, 2018: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29545601/tdp43-nuclear-export-and-neurodegeneration-in-models-of-amyotrophic-lateral-sclerosis-and-frontotemporal-dementia
#12
Hilary C Archbold, Kasey L Jackson, Ayush Arora, Kaitlin Weskamp, Elizabeth M-H Tank, Xingli Li, Roberto Miguez, Robert D Dayton, Sharon Tamir, Ronald L Klein, Sami J Barmada
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders marked in most cases by the nuclear exclusion and cytoplasmic deposition of the RNA binding protein TDP43. We previously demonstrated that ALS-associated mutant TDP43 accumulates within the cytoplasm, and that TDP43 mislocalization predicts neurodegeneration. Here, we sought to prevent neurodegeneration in ALS/FTD models using selective inhibitor of nuclear export (SINE) compounds that target exportin-1 (XPO1)...
March 15, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29527542/immunoprecipitation-of-tri-methylated-capped-rna
#13
Karen E Hayes, Jamie A Barr, Mingyi Xie, Joan A Steitz, Ivan Martinez
Cellular quiescence (also known as G0 arrest) is characterized by reduced DNA replication, increased autophagy, and increased expression of cyclin-dependent kinase p27Kip1 . Quiescence is essential for wound healing, organ regeneration, and preventing neoplasia. Previous findings indicate that microRNAs (miRNAs) play an important role in regulating cellular quiescence. Our recent publication demonstrated the existence of an alternative miRNA biogenesis pathway in primary human foreskin fibroblast (HFF) cells during quiescence...
February 5, 2018: Bio-protocol
https://www.readbyqxmd.com/read/29526737/klf4-nuclear-export-requires-erk-activation-and-initiates-exit-from-naive-pluripotency
#14
Navroop K Dhaliwal, Kamelia Miri, Scott Davidson, Hala Tamim El Jarkass, Jennifer A Mitchell
Cooperative action of a transcription factor complex containing OCT4, SOX2, NANOG, and KLF4 maintains the naive pluripotent state; however, less is known about the mechanisms that disrupt this complex, initiating exit from pluripotency. We show that, as embryonic stem cells (ESCs) exit pluripotency, KLF4 protein is exported from the nucleus causing rapid decline in Nanog and Klf4 transcription; as a result, KLF4 is the first pluripotency transcription factor removed from transcription-associated complexes during differentiation...
April 10, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/29501729/stat6-is-a-cargo-of-exportin-1-biological-relevance-in-primary-mediastinal-b-cell-lymphoma
#15
Hadjer Miloudi, Karen Leroy, Fabrice Jardin, Brigitte Sola
Primary mediastinal B-cell lymphoma (PMBL) is a distinct B-cell lymphoma subtype with unique clinicopathological and molecular features. PMBL cells are characterised by several genetic abnormalities that conduct to the constitutive activation of the Janus kinase 2/signal transducer and activator of transcription 6 (JAK2/STAT6) signalling pathway. Among recurrent genetic changes in PMBL, we previously reported that the XPO1 gene encoding exportin 1 that controls the nuclear export of cargo proteins and RNAs, is mutated (p...
June 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29381435/selective-inhibition-of-nuclear-export-with-oral-selinexor-for-treatment-of-relapsed-or-refractory-multiple-myeloma
#16
Dan T Vogl, David Dingli, Robert Frank Cornell, Carol Ann Huff, Sundar Jagannath, Divaya Bhutani, Jeffrey Zonder, Rachid Baz, Ajay Nooka, Joshua Richter, Craig Cole, Ravi Vij, Andrzej Jakubowiak, Rafat Abonour, Gary Schiller, Terri L Parker, Luciano J Costa, David Kaminetzky, James E Hoffman, Andrew J Yee, Ajai Chari, David Siegel, Rafael Fonseca, Scott Van Wier, Gregory Ahmann, Ilsel Lopez, Michael Kauffman, Sharon Shacham, Jean-Richard Saint-Martin, Carla D Picklesimer, Cassandra Choe-Juliak, A Keith Stewart
Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease)...
March 20, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
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/29358183/clinical-implications-of-cancer-gene-mutations-in-patients-with-chronic-lymphocytic-leukemia-treated-with-lenalidomide
#18
Koichi Takahashi, Boyu Hu, Feng Wang, Yuanqing Yan, Ekaterina Kim, Candida Vitale, Keyur P Patel, Paolo Strati, Curtis Gumbs, Latasha Little, Samantha Tippen, Xingzhi Song, Jianhua Zhang, Nitin Jain, Philip Thompson, Guillermo Garcia-Manero, Hagop Kantarjian, Zeev Estrov, Kim-Anh Do, Michael Keating, Jan A Burger, William G Wierda, P Andrew Futreal, Alessandra Ferrajoli
Lenalidomide is clinically active in chronic lymphocytic leukemia (CLL), but its effectiveness in the context of the CLL mutational landscape is unknown. We performed targeted capture sequencing of 295 cancer genes in specimens from 102 CLL patients with treatment-naïve disease (TN patients) and 186 CLL patients with relapsed/refractory disease (R/R patients) who received lenalidomide-based therapy at our institution. The most frequently mutated gene was SF3B1 (15%), followed by NOTCH1 (14%) and TP53 (14%), with R/R patients having significantly more TP53 mutations than did TN patients...
April 19, 2018: Blood
https://www.readbyqxmd.com/read/29321689/analysis-of-combined-transcriptomes-identifies-gene-modules-that-differentially-respond-to-pathogenic-stimulation-of-vascular-smooth-muscle-and-endothelial-cells
#19
Xiaokang Pan, Bowen Wang, Tiezheng Yuan, Mengxue Zhang, K Craig Kent, Lian-Wang Guo
Smooth muscle cells (SMCs) and endothelial cells (ECs) are vital cell types composing the vascular medial wall and the atheroprotective inner lining, respectively. Current treatments for cardiovascular disease inhibit SMC hyperplasia but compromise EC integrity, predisposing patients to thrombosis. Therapeutics targeting SMCs without collateral damage to ECs are highly desirable. However, differential (SMC versus EC) disease-associated regulations remain poorly defined. We conducted RNA-seq experiments to investigate SMC-versus-EC differential transcriptomic dynamics, following treatment of human primary SMCs and ECs with TNFα or IL-1β, both established inducers of SMC hyperplasia and EC dysfunction...
January 10, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29321323/hiv-1-vif-s-capacity-to-manipulate-the-cell-cycle-is-species-specific
#20
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
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