Prelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion

Referencia

Nature Communications (2013) 4:2268 doi: 10.1038/ncomms3268. PMID: 23917225

Autores

Jorge de la Rosa, José M.P. Freije, Rubén Cabanillas, Fernando G. Osorio, Mario F. Fraga, M. Soledad Fernández-García, Roland Rad, Víctor Fanjul, Alejandro P. Ugalde, Qi Liang, Haydn M. Prosser, Allan Bradley, Juan Cadiñanos y Carlos López-Otín

Resumen

Defining the relationship between ageing and cancer is a crucial but challenging task. Mice deficient in Zmpste24, a metalloproteinase mutated in human progeria and involved in nuclear prelamin A maturation, recapitulate multiple features of ageing. However, their short lifespan and serious cell-intrinsic and cell-extrinsic alterations restrict the application and interpretation of carcinogenesis protocols. Here we present Zmpste24 mosaic mice that lack these limitations. Zmpste24 mosaic mice develop normally and keep similar proportions of Zmpste24-deficient (prelamin A-accumulating) and Zmpste24-proficient (mature lamin A-containing) cells throughout life, revealing that cell-extrinsic mechanisms are preeminent for progeria development. Moreover, prelamin A accumulation does not impair tumour initiation and growth, but it decreases the incidence of infiltrating oral carcinomas. Accordingly, silencing of ZMPSTE24 reduces human cancer cell invasiveness. Our results support the potential of cell-based and systemic therapies for progeria and highlight ZMPSTE24 as a new anticancer target.

Descripción

La lamina A es una proteína de la envuelta nuclear producida por la maduración de su precursor, prelamina A, catalizada por la proteasa ZMPSTE24. La acumulación de precursores de la lamina A, debida a la ausencia de ZMPSTE24 o a mutaciones en el gen LMNA, desencadena enfermedades de envejecimiento acelerado, como la progeria de Hutchinson-Gilford. Estos precursores también se han relacionado con el envejecimiento normal. En este trabajo generamos ratones mosaicos de Zmpste24, y comprobamos que los principales mecanismos responsables de estas enfermedades son extrínsecos a la célula, lo cual apoya el empleo de terapias sistémicas para tratarlas. Además, demostramos que la prelamina A frena la invasión tumoral, lo cual sugiere que Zmpste24 es una posible diana antitumoral.

grupo

REFERENCIA DEL GRUPO INVESTIGADOR

Los ratones deficientes en ZMPSTE24, que desarrollan envejecimiento acelerado, fueron generados en el laboratorio de Carlos López-Otín en la Universidad de Oviedo, hace más de una década, dentro del trabajo de tesis doctoral de Juan Cadiñanos. Ese fue el punto de partida de una productiva línea de investigación que ha permitido importantes avances en el conocimiento y el tratamiento de las enfermedades que cursan con envejecimiento acelerado. El presente trabajo es una colaboración entre los laboratorios de López-Otín y Juan Cadiñanos, del Instituto de Medicina Oncológica y Molecular de Asturias, y forma parte del proyecto de tesis doctoral de Jorge de la Rosa, que explora los mecanismos responsables del envejecimiento acelerado y sus conexiones con el cáncer.

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Lanuza-Masdeu Jordi, Arévalo María Isabel, Vila Cristina, Barberà Albert, Gomis Ramon, Caelles Carme.
Germinal centre protein HGAL promotes lymphoid hyperplasia and amyloidosis via BCR-mediated Syk activation
Isabel Romero Camarero, Xiaoyu Jiang, Yasodha Natkunam, Xiaoqing Lu, Carolina Vicente Dueñas, Ines González Herrero, Teresa Flores, Juan Luis García, George McNamara, Christian Kunder, Shuchun Zhao, Víctor Segura, Lorena Fontán…

Exploring new biological functions of amyloids: bacteria cell agglutination mediated by host protein aggregation.
Marc Torrent, David Pulido, Maria VictòriaNogués, Ester Boix.
Prochlorococcus can use the Pro1404 transporter to take up glucose at nanomolar concentrations in the Atlantic Ocean
Muñoz-Marin MC, Luque I, Zubkov MV, Hill PG, Diez J & García-Fernandez JM
Cytoneme-Mediated Delivery of Hedgehog Regulates the Expression of Bone Morphogenetic Proteins to Maintain Germline Stem Cells in Drosophila
Patricia Rojas Ríos, Isabel Guerrero Vega y Acaimo González Reyes.
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…