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.

Did you publish an interesting article recently?

Send it through our application form and we will contact you. Age limit: 32.

The selected articles will participate at the Award to the best article of young people of the SEBBM which will be given during SEBBM conference, that will take place at Spain (free registration, travel and accommodation).

More articles of the month

The structure of a polygamous repressor reveals how phage-inducible chromosomal islands spread in nature

01-11-2019

Stl is a master repressor encoded by Staphylococcus aureus pathogenicity islands (SaPIs) that maintains integration of these elements in the bacterial chromosome. After infection or induction of a resident helper...

Read more

Self-Assembling ELR-Based Nanoparticles as Smart Drug-Delivery Systems Modulating Cellular Growth via Akt

01-10-2019

This work investigates the physicochemical properties and in vitro accuracy of a genetically engineered drug delivery system based on elastin-like block recombinamers. The DNA recombinant technics allowed us to create...

Read more

Structure–Function of MamC Loop and Its Effect on the *in Vitro* Precipitation of Biomimetic Magnetite Nanoparticles

01-09-2019

MamC, an integral protein of the magnetosome membrane, has recently been proposed as a strong candidate to produce biomimetic (magnetosome-like) magnetite nanoparticles that could be used as an alternative to...

Read more

Sticholysin, Sphingomyelin, and Cholesterol: A Closer Look at a Tripartite Interaction

01-08-2019

Actinoporins are a group of soluble toxic proteins that bind to membranes containing sphingomyelin (SM) and oli- gomerize to form pores. Sticholysin II (StnII) is a member of the actinoporin...

Read more

Astrocytic mitochondrial ROS modulate brain metabolism and mouse behaviour

01-07-2019

To satisfy its high energetic demand, the brain depends on the metabolic cooperation of various cell types. For example, astrocytic-derived lactate sustains memory consolidation by serving both as an oxidizable...

Read more

Glucose restriction promotes osteocyte specification by activating a PGC-1α-dependent transcriptional program

03-06-2019

Osteocytes, the most abundant of bone cells, differentiate while they remain buried within the bone matrix. This encasement limits their access to nutrients and likely affects their differentiation, a process...

Read more

ParB dynamics and the critical role of the CTD in DNA condensation unveiled by combined force-fluorescence measurements

01-05-2019

/Bacillus subtilis/ ParB forms multimeric networks involving non-specific DNA binding leading to DNA condensation. Previously, we found that an excess of the free C-terminal domain (CTD) of ParB impeded DNA...

Read more

Therapeutic targeting of HER2-CB2R heteromers in HER2-positive breast cancer

01-04-2019

Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New...

Read more

p73 regulates ependymal planar cell polarity by modulating actin and microtubule cytoskeleton

01-03-2019

Planar cell polarity (PCP) and intercellular junctional complexes establish tissue structure and coordinated behaviors across epithelial sheets. In multiciliated ependymal cells, rotational and translational PCP coordinate cilia beating and direct...

Read more

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...

Read more

Protector Members