A Genetic Defect in Exportin-5 Traps Precursor MicroRNAs in the Nucleus of Cancer Cells

Referencia

Cancer Cell (2010) 18: 303–315

Autores

Melo SA, Moutinho C, Ropero S, Calin GA, Rossi S, Spizzo R, Fernandez AF, Davalos V, Villanueva A, Montoya G, Yamamoto H, Schwartz Jr, Esteller M.

Resumen

El articulo revela que un subgrupo de tumores del colon, estómago y útero secuestran precursores de microRNAs dentro del núcleo no podiendo progredir su biogenesis hasta microRNAs maduros. Los tumores descritos presentan una mutación en una proteína denominada Exportina-5 que en una celula sana actúa como taxista llevando los microRNAs desde el núcleo al citoplasma, pero en estos cánceres es incapaz de conducirlos fuera del núcleo por lo que se pierde su capacidad protectora antitumoral y se observa una disregulacion general de los microRNAs maduros en estas células tumorales.

Descripción

The global impairment of mature microRNAs (miRNAs) is emerging as a common feature of human tumors. One interesting scenario is that defects in the nuclear export of precursormiRNAs (pre-miRNAs) might occur in transformed cells. Exportin 5 (XPO5) mediates pre-miRNA nuclear export and herein we demonstrate the presence of XPO5-inactivating mutations in a subset of human tumors with microsatellite instability. The XPO5 genetic defect traps pre-miRNAs in the nucleus, reduces miRNA processing, and diminishes miRNA-target inhibition. The XPO5 mutant form lacks a C-terminal region that contributes to the formation of the pre-miRNA/XPO5/Ran-GTP ternary complex and pre-miRNAs accumulate in the nucleus. Most importantly, the restoration of XPO5 functions reverses the impaired export of pre-miRNAs and has tumor suppressor features.

Imágen artículo Diciembre

REFERENCIA DEL GRUPO E INVESTIGADOR
Sónia Melo ha realizado la tesis doctoral en el laboratorio de Epigenética del Cáncer dirigido por el Dr. Manel Esteller en el Instituto de Investigación Biomédica de Bellvitge (IDIBELL), Barcelona. Su investigación ha estado centrada en las alteraciones genéticas y epigenéticas que afectan la actividad de los microRNAs en cáncer humano.

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PRESYNAPTIC SELF-DEPRESSION AT DEVELOPING NEOCORTICAL SYNAPSES
Antonio Rodríguez-Moreno, Ana González-Rueda, Abhishek Banerjee, A. Louise Upton, Michael T. Craig MT and Ole Paulsen
Glucose-Induced β-Catenin Acetylation Enhances Wnt Signaling in Cancer
Ana Chocarro-Calvo, Jose Manuel García-Martínez, Soraya Ardila-González, Antonio De la Vieja and Custodia García-Jiménez
Nek9 phosphorylation of NEDD1/GCP-WD contributes to Plk1 control of gamma-tubulin recruitment to the mitotic centrosome
Sdelci S*, Schütz M*, Pinyol R, Bertran MT, Regué L, Caelles C, Vernos I, Roig J. (*These authors contributed equally to this work)
CDK2-dependent activation of PARP-1 is required for hormonal gene regulation in breast cancer cells
Roni H. G. Wright, Giancarlo Castellano, Jaume Bonet, Francois Le Dily, Jofre Font-Mateu, Cecilia Ballaré, A. Silvina Nacht, Daniel Soronellas1, Baldo Oliva and Miguel Beato(CRG, Barcelona)
Expression of MALT1 oncogene in hematopoietic stem/progenitor cells recapitulates the pathogenesis of human lymphoma in mice.
Vicente-Duenas, C., L. Fontan, I. Gonzalez-Herrero, I. Romero-Camarero, V. Segura, M.A. Aznar, E. Alonso-Escudero, E. Campos-Sanchez, L. Ruiz-Roca, M. Barajas-Diego, A. Sagardoy, J.I. Martinez-Ferrandis, F. Abollo-Jimenez, C. Bertolo, I. Penuelas…
Un RNA viroidal redirige a la DNA ligasa 1 del huésped a actuar como RNA ligasa
María-Ángeles Nohales, Ricardo Flores y José-Antonio Daròs
β-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer
Stephan P Tenbaum, Paloma Ordóñez-Morán, Isabel Puig, Irene Chicote, Oriol Arqués, Stefania Landolfi, Yolanda Fernández, José Raúl Herance, Juan D Gispert, Leire Mendizabal, Susana Aguilar, Santiago Ramón y Cajal, Simó…

A role for tRNA modifications in genome structure and codon usage
Eva Maria Novoa, Mariana Pavon-Eternod, Tao Pan, Lluis Ribas de Pouplana
γ-Glutamylcysteine detoxifes reactive oxygen species by acting as glutathione peroxidase-1 cofactor
Quintana-Cabrera, R.; Fernández-Fernández, S.; Bobo-Jiménez, V.; Escobar, J.; Sastre, J; Almeida, A.; Bolaños, J.P.
Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis.
Sebastián D*, Hernández-Alvarez MI*, Segalés J*, Sorianello E, Muñoz JP, Sala D, Waget A, Liesa M, Paz JC, Gopalacharyulu P, Oresic M, Pich S, Burcelin R, Palacín M, Zorzano A…
Molecular therapy for obesity and diabetes based on a long-term increase in hepatic fatty-acid oxidation
Josep M. Orellana-Gavaldà, Laura Herrero, Maria Ida Malandrino, Astrid Pañeda, María Sol Rodríguez-Peña, Harald Petry, Guillermina Asins, Sander Van Deventer, Fausto G. Hegardt, Dolors Serra.
A novel GRK2/HDAC6 interaction modulates cell spreading and motility
Vanesa Lafarga, Ivette Aymerich, Olga Tapia, Federico Mayor Jr, Petronila Penela
Regulation of Ribonucleotide Reductase in Response to Iron Deficiency
Nerea Sanvisens, Mari Carmen Bañó, Mingxia Huang y Sergi Puig
Methionine adenosyltransferase 1A gene deletion disrupts hepatic very low-density lipoprotein assembly in mice
Ainara Cano, Xabier Buqué, Maite Martínez-Uña, Igor Aurrekoetxea, Ariane Menor, Juan Luis García-Rodríguez2, Shelly Lu, José María Mato, Begoña Ochoa y Patricia Aspichueta
Human mitochondrial transcription factor A induces a U-turn structure in the light strand promoter
Rubio-Cosials A, Sidow JF, Jiménez-Menéndez N, Fernández-Millán P, Montoya J, Jacobs HT, Coll M, Bernadó P, Solà M.
Intramolecular signal transmission in a tetrameric repressor of the IclR family
Fillet S, Krell T, Morel B, Lu D, Zhang X, Ramos JL.
Neurodegeneration and functional impairments associated with glycogen synthase accumulation in a mouse model of Lafora disease
Valles-Ortega J*, Duran J*, Garcia-Rocha M, Bosch C, Saez I, Pujadas L, Serafin A, Cañas X, Soriano E, Delgado-García JM, Gruart A, Guinovart JJ. * Coautores

Control of Ubp3 ubiquitin protease activity by the Hog1 SAPK modulates transcription upon osmostress
Carme Solé1,3, Mariona Nadal-Ribelles1,3, Claudine Kraft2, Matthias Peter2, Francesc Posas1 and Eulàlia de Nadal1 1. Departament de Ciències Experimentals i de la Salut, Cell Signalling Unit, Universitat Pompeu Fabra (UPF)…
Autophagy promotes survival of retinal ganglion cells after optic nerve axotomy in mice
Natalia Rodríguez-Muela, Francisco Germain, Guillermo Mariño, Patrick S Fitze and Patricia Boya.
Drosophila lipophorin recpetors mediate the uptake of neutral lipids in oocytes and imaginal disc cells by an endocytosis-independent mechanism
Esmeralda Parra-Peralbo y Joaquim Culí
Light-dependent gene regulation by a coenzyme B12-based photoreceptor
Juan Manuel Ortiz-Guerrero, María Carmen Polanco, Francisco J. Murillo, S. Padmanabhan, y Montserrat Elías-Arnanz
Small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing
Melo S, Villanueva A, Moutinho C, Davalos V, Spizzo R, Ivan C, Rossi S, Setien F, Casanovas O, Simo-Riudalbas L, Carmona J, Carrere J, Vidal A, Aytes A, Puertas S…
Structure of a Preternary Complex Involving a Prokaryotic NHEJ DNA Polymerase
Nigel C. Brissett*, Maria Jose Martin*, Robert S. Pitcher, Julie Bianchi, Raquel Juarez, Andrew J. Green, Gavin C. Fox, Luis Blanco', and Aidan J. Doherty'. (* coauthors) ('co-corresponding authors)
Crystal structure of the open conformation of the mammalian chaperonin CCT in complex with tubulin
Muñoz IG, Yébenes H, Zhou M, Mesa P, Serna M, Park AY, Bragado-Nilsson E, Beloso A, de Cárcer G, Malumbres M, Robinson CV, Valpuesta JM, Montoya G.
Targeting mitotic exit leads to tumor regression in vivo: Modulation by Cdk1, Mastl, and the PP2A/B55α,δ phosphatase
Manchado E, Guillamot M, de Cárcer G, Eguren M, Trickey M, García-Higuera I, Moreno S, Yamano H, Cañamero M, Malumbres M.
Distributed Biological Computation with Multicellular Engineered Networks
Sergi Regot*, Javier Macia*, Núria Conde, Kentaro Furukawa, Jimmy Kjellén, Tom Peeters, Stefan Hohmann, Eulàlia de Nadal, Francesc Posas* y Ricard Solé*
A Genetic Defect in Exportin-5 Traps Precursor MicroRNAs in the Nucleus of Cancer Cells
Melo SA, Moutinho C, Ropero S, Calin GA, Rossi S, Spizzo R, Fernandez AF, Davalos V, Villanueva A, Montoya G, Yamamoto H, Schwartz Jr, Esteller M.

Endocannabinoids potentiate synaptic transmission through stimulation of astrocytes
Marta Navarrete and Alfonso Araque
Structure and inhibition of herpesvirus DNA packaging terminase nuclease domain
Marta Nadal, Philippe Mas, Alexandre G. Blanco, Carme Arnan, Maria Solà, Darren J. Hart y Miquel Coll
Structural basis for the wobbler mouse neurodegenerative disorder caused by mutation in the Vps54 subunit of the GARP complex
F. Javier Pérez-Victoria(1)*, Guillermo Abascal-Palacios(2)*, Igor Tascón(2), Andrey Kajava(3), Javier G. Magadán(1), Erik P. Pioro(4), Juan S. Bonifacino(1), Aitor Hierro(2) *Equal contribution. (1) Cell Biology and Metabolism Program, Eunice Kennedy Shriver National…
Human mitochondrial mTERF wraps around DNA through a left-handed superhelical tandem repeat
Nereida Jiménez-Menéndez1,2, Pablo Fernández-Millán1, Anna Rubio-Cosials1, Carme Arnan1,2, Julio Montoya3, Howard T Jacobs4, Pau Bernadó2, Miquel Coll1,2, Isabel Usón1,5 & Maria Solà1
Retinoid X receptor α controls innate inflammatory responses through the up-regulation of chemokine expression
Vanessa Núñeza,1, Daniel Alamedaa,1, Daniel Ricoa,2, Rubén Motab, Pilar Gonzalob, Marta Cedenillaa, Thierry Fischerc, Lisardo Boscád, Christopher K. Glasse, Alicia G. Arroyob, and Mercedes Ricotea,3 Departments of aRegenerative Cardiology and bVascular…
Cysteine string protein-α prevents activity-dependent degeneration in GABAergic synapses
Pablo García-Junco-Clemente , Gloria Cantero ,Leonardo Gómez-Sánchez , Pedro Linares-Clemente, Jose A. Martínez-López , Rafael Luján, Rafael Fernández-Chacón.
A Postincision-Deficient TFIIH Causes Replication Fork Breakage and Uncovers Alternative Rad51- or Pol32-Mediated Restart Mechanisms
María Moriel-Carretero* y Andrés Aguilera* *Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla-CSIC, Sevilla, Spain
Moonlighting proteins Hal3 and Vhs3 form a heteromeric PPCDC with Ykl088w in yeast CoA biosynthesis
Amparo Ruiz1,4,7, Asier González1,2,7, Ivan Muñoz1,5, Raquel Serrano1,6, J Albert Abrie3, Erick Strauss3 and Joaquín Ariño1,2 1. Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain. 2. Institut de Biotecnologia i…
The insect nephrocyte is a podocyte-like cell with a filtration slit diaphragm
Weavers*, H., Prieto-Sánchez*, S., Grawe, F., García-López, A.,Artero,R.,F. Wilsch-Braeuninger, M., Ruiz-Gómez, M., Skaer, H. y Delholm, B.
The asymmetric / symmetric activation of GPCR dimers as a possible mechanistic rationale for multiple signalling pathways
Xavier Rovira (1), Jean-Philippe Pin (2) and Jesús Giraldo (1) 1- Laboratory of Systems Pharmacology and Bioinformatics, Institut de Neurociencies and Unitat de Bioestadıstica, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain. 2-…

The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C–Cdh1
Herrero-Méndez, A.; Almeida, A.; Fernández, E.; Maestre, C.; Moncada, S.; y Bolaños, J.P.
The mechanism of vault opening from the high resolution structure of the N-terminal repeats of MVP.
Querol-Audí J, Casañas A, Usón I, Luque D, Castón JR, Fita I, Verdaguer N.
Overactivation of the MEK/ERK Pathway in Liver Tumor Cells Confers Resistance to TGF-B–Induced Cell
Laia Caja, Patricia Sancho, Esther Bertran, Daniel Iglesias-Serret, Joan Gil, Isabel Fabregat
A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function
Sonia A. Melo(1), Santiago Ropero(1), Catia Moutinho(1), Lauri A Aaltonen(2), Hiroyuki Yamamoto(3), George A Calin(4), Simona Rossi(4), Agustin F Fernandez(1), Fatima Carneiro(5), Carla Oliveira(5), Bibiana Ferreira(1), Chang-Gong Liu(4), Alberto Villanueva(6)…
A molecular framework for light and gibberellin control of cell elongation.
Miguel de Lucas1,4, Jean-Michel Davière1,4, Mariana Rodríguez-Falcón1,4, Mariela Pontin1, Juan Manuel Iglesias-Pedraz1, Séverine Lorrain2, Christian Fankhauser2, Miguel Angel Blázquez3, Elena Titarenko1 & Salomé Prat1 Departamento de Genética Molecular de Plantas…