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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
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...
February 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
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 as well as 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...
February 19, 2018: Biochemical Journal
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
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
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...
January 31, 2018: Molecular Cell
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
Arzu Ulu, Wonkyung Oh, Yan Zuo, Jeffrey A Frost
The Neuroepithelial cell transforming gene 1A (Net1A) is a RhoA subfamily 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 Net1A cytosolic relocalization. We demonstrate that inhibition of MAPK pathways blocks Net1A relocalization, with cells being most sensitive to JNK pathway inhibition. Moreover, JNK or p38 MAPK activation is sufficient to elicit Net1A cytosolic localization...
December 19, 2017: Journal of Cell Science
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
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
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
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...
February 2018: Biochimica et Biophysica Acta
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...
January 2018: Biochemical Pharmacology
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
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
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
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...
January 1, 2018: Virology
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
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
Anna M 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...
December 1, 2017: Journal of Biological Chemistry
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