Referencia

Nature Genetics 41, 365 - 370 (2009) Published online: 15 February 2009 | doi:10.1038/ng.317

Autores

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), Gabriel Capella(6), Simo Schwartz Jr(7), Ramin Shiekhattar(8,9) & Manel Esteller(1,9,10)

Resumen

El artículo describe la alteración del gen TARBP2, presente en el 25% de los tumores de colon, estómago y útero de la ruta mutadora. El gen TARBP2 es clave en la regulación de muchos otros genes al tratarse del gen que fabrica los microRNAs, pequeñas moleculas de acido ribonucleico (ARN) que actuan como interruptores de la expresión genética. Es la primera vez que se demuestra la existencia de alteraciones en un gen de la cadena de montaje de los microRNAs en tumores humanos. La mutación descubierta inactiva el gen TARBP2 y se produce tanto en casos hereditarios de la enfermedad como en cánceres esporádicos. Además, las células que poseen esta alteración presentan una actividad aberrante de muchos otros genes debido a que TARBP2 actúa a modo de guardia de tráfico, regulando la actividad posterior de muchísimos otros genes.

Descripción

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by targeting messenger RNA (mRNA) transcripts. Recently, a miRNA expression profile of human tumors has been characterized by an overall miRNA downregulation (1, 2, 3). Explanations for this observation include a failure of miRNA post-transcriptional regulation (4), transcriptional silencing associated with hypermethylation of CpG island promoters (5, 6, 7) and miRNA transcriptional repression by oncogenic factors (8). Another possibility is that the enzymes and cofactors involved in miRNA processing pathways may themselves be targets of genetic disruption, further enhancing cellular transformation (9). However, no loss-of-function genetic alterations in the genes encoding these proteins have been reported. Here we have identified truncating mutations in TARBP2 (TAR RNA-binding protein 2), encoding an integral component of a DICER1-containing complex (10, 11) in sporadic and hereditary carcinomas with microsatellite instability (12, 13, 14). The presence of TARBP2 frameshift mutations causes diminished TRBP protein expression and a defect in the processing of miRNAs. The reintroduction of TRBP in the deficient cells restores the efficient production of miRNAs and inhibits tumor growth. Most important, the TRBP impairment is associated with a destabilization of the DICER1 protein. These results provide, for a subset of human tumors, an explanation for the observed defects in the expression of mature miRNAs.

1. Cancer Epigenetics Laboratory, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
2. Tumor Genomics Group, Academy of Finland and Genome-Scale Biology Research Program/Biomedicum, Department of Medical Genetics, University of Helsinki F-00014 Helsinki, Finland.
3. Sapporo Medical University, South 1, West 17, Chuo-ku, Sapporo 060-8556, Japan.
4. Experimental Therapeutics & Cancer Genetics, MD Anderson Cancer Center, Houston, Texas 77030, USA.
5. Medical Faculty of the University of Porto and Hospital S. João and Institute of Molecular Pathology and Immunology (IPATIMUP), 4200-465 Porto, Portugal.
6. Translational Research Laboratory, IDIBELL-Institut Catala d'Oncologia, 08907 Barcelona, Spain.
7. Molecular Biology and Biochemistry Research Center for Nanomedicine, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, 08035 Barcelona, Catalonia, Spain.
8. Center for Genomic Regulation, C/Dr. Aiguader 88, 08003 Barcelona, Catalonia, Spain.

Imágen artículo Noviembre

Sónia Melo realiza la tesis doctoral en el laboratorio de Epigenética del Cancer dirigido por el Dr Manel Esteller en el Instituto de Investigacion Biomédica de Bellvitge (IDIBELL) , Hospitalet, Barcelona. Su investigacion está centrada en las alteraciones genéticas y epigenéticas que afectan la actividad de los microRNAs en cáncer humano.

Descárgate este artículo aquí.
Más artículos en la revista SEBBM.

¿Acabas de publicar un artículo interesante?

Manda la referencia a través de nuestro formulario.  Límite de edad 32 años. Los artículos seleccionados serán destacados como artículos del mes y participarán en el Premio al mejor artículo de jóvenes de la SEBBM, que se entregará en el congreso de la SEBBM (inscripción y alojamiento gratuitos).

Otros "Artículos del mes"

β‐RA reduces DMQ/CoQ ratio and rescues the encephalopathic phenotype in Coq9R239X mice

01-02-2019

Coenzyme Q (CoQ) deficiency has been associated with primary defects in the CoQ biosynthetic pathway or to secondary events. In some cases, the exogenous CoQ supplementation has limited efficacy. In...

Leer más

Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons

02-01-2019

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of...

Leer más

Dynamic acetylation of cytosolic phosphoenolpyruvate carboxykinase toggles enzyme activity between gluconeogenic and anaplerotic reactions

01-12-2018

Cytosolic phosphoenolpyruvate carboxykinase (PCK1) is considered a gluconeogenic enzyme; however, its metabolic functions and regulatory mechanisms beyond gluconeogenesis are poorly understood. Here, we describe that dynamic acetylation of PCK1 interconverts...

Leer más

The Helicase PIF1 Facilitates Resection overSequences Prone to Forming G4 Structures

02-11-2018

DNA breaks are complex lesions that can be repaired either by non-homologous end joining (NHEJ) or by homologous recombination (HR). The decision between these two routes of DNA repair is...

Leer más

Preventing loss of mechanosensation by the nuclear membranes of alveolar cells reduces lung injury in mice during mechanical ventilation

01-10-2018

The nuclear membrane acts as a mechanosensor that drives cellular responses following changes in the extracellular environment. Mechanically ventilated lungs are exposed to an abnormally high mechanical load that may...

Leer más

Oxidative stress is tightly regulated by cytochrome c phosphorylation and respirasome factors in mitochondria

03-09-2018

Respiratory cytochrome c has been found to be phosphorylated at tyrosine 97 in the postischemic brain upon neuroprotective insulin treatment, but how such posttranslational modification affects mitochondrial metabolism is unclear...

Leer más

STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis

01-08-2018

The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of...

Leer más

A broad atlas of somatic hypermutation allows prediction of activation-induced deaminase targets

02-07-2018

Activation-induced deaminase (AID) initiates antibody diversification in germinal center (GC) B cells through the deamination of cytosines on immunoglobulin genes. AID can also target other regions in the genome, triggering...

Leer más

Deciphering the Dynamic Transcriptional and Post-transcriptional Networks of Macrophages in the Healthy Heart and after Myocardial Injury

01-06-2018

Our group is interested in the behavior and transcriptional regulation of macrophages in the context of complex disease environments. We have generated a whole transcriptome dataset (mRNA, miRNA, and lincRNA)...

Leer más

Synaptic activity‐induced glycolysis facilitates membrane lipid provision and neurite outgrowth

01-05-2018

La formación de nuevas neuritas es un proceso clave para el correcto desarrollo del sistema nervioso. El crecimiento neurítico requiere la generación de nuevas membranas. No obstante, los cambios metabólicos...

Leer más

Socios Protectores