Suchergebnisse

The regulation of gene expression by microRNAs (miRNAs) is critical for normal development and physiology. Conversely, miRNA function is frequently impaired in cancer, and other pathologies, either by aberrant expression of individual miRNAs or dysregulation of miRNA synthesis. Here, we have investigated the impact of global disruption of miRNA biogenesis in primary fibroblasts of human or murine origin, through the knockdown of DGCR8, an essential mediator of the synthesis of canonical miRNAs. We find that the inactivation of DGCR8 in these cells results in a dramatic antiproliferative response, with the acquisition of a senescent phenotype. Senescence triggered by DGCR8 loss is accompanied by the upregulation of the cell-cycle inhibitor p21CIP1. We further show that a subset of senescence-associated miRNAs with the potential to target p21CIP1 is downregulated during DGCR8-mediated senescence. Interestingly, the antiproliferative response to miRNA biogenesis disruption is retained in human tumor cells, irrespective of p53 status. In summary, our results show that defective synthesis of canonical microRNAs results in cell-cycle arrest and cellular senescence in primary fibroblasts mediated by specific miRNAs, and thus identify global miRNA disruption as a novel senescence trigger. © 2013 The Anatomical Society and John Wiley & Sons Ltd. ; This work was supported by grants SAF2009-09031 and SAF2012-32117 from the Spanish Government to IP, and core support from MRCand grants from MRCT, CRUK, AICR, and the EMBO Young Investigator Programme to JG. We are grateful to Manuel Serrano and Daniel Peeperfor reagents and advice, and to Pablo Huertas for help with DDR assays. ; Peer Reviewed

33 Pags.- 1 Tabl.- 16 Figs. Creative Commons Attribution License. ; We analyzed potential land degradation processes in semiarid regions worldwide using long time series of remote sensing images and the Normalized Difference Vegetation Index (NDVI) for the period 1981 to 2011. The objectives of the study were to identify semiarid regions showing a marked decrease in potential vegetation activity, indicative of the occurrence of land degradation processes, and to assess the possible influence of the observed drought trends quantified using the Standardized Precipitation Evapotranspiration Index (SPEI). We found that the NDVI values recorded during the period of maximum vegetation activity (NDVImax) predominantly showed a positive evolution in the majority of the semiarid regions assessed, but NDVImax was highly correlated with drought variability, and the trends of drought events influenced trends in NDVImax at the global scale. The semiarid regions that showed most increase in NDVImax (the Sahel, northern Australia, South Africa) were characterized by a clear positive trend in the SPEI values, indicative of conditions of greater humidity and lesser drought conditions. While changes in drought severity may be an important driver of NDVI trends and land degradation processes in semiarid regions worldwide, drought did not apparently explain some of the observed changes in NDVImax. This reflects the complexity of vegetation activity processes in the world's semiarid regions, and the difficulty of defining a universal response to drought in these regions, where a number of factors (natural and anthropogenic) may also affect on land degradation. ; This work was supported by the research projects CGL2011-27574-CO2-02, CGL2011-24185, CGL2014-52135-C03-01 and Red de variabilidad y cambio climático RECLIM (CGL2014-517221-REDT) financed by the Spanish Commission of Science and Technology and FEDER and "LIFE12 ENV/ES/000536-Demonstration and validation of innovative methodology for regional climate change adaptation in the Mediterranean area (LIFE MEDACC)" financed by the LIFE programme of the European Commission. Cesar Azorin-Molina was supported by the JCI-2011-10263 grant. Miquel Tomas-Burguera was supported by a doctoral grant by the Ministry of Economy and Competitiveness and Natalia Martin-Hernandez was supported by a doctoral grant by the Aragón Regional Government. We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI). ; Peer reviewed