Garcia-Cerro S.,University of Cantabria |
Martinez P.,University of Cantabria |
Vidal V.,University of Cantabria |
Corrales A.,University of Cantabria |
And 6 more authors.
PLoS ONE | Year: 2014
Down syndrome (DS) phenotypes result from the overexpression of several dosage-sensitive genes. The DYRK1A (dualspecificity tyrosine-(Y)-phosphorylation regulated kinase 1A) gene, which has been implicated in the behavioral and neuronal alterations that are characteristic of DS, plays a role in neuronal progenitor proliferation, neuronal differentiation and long-term potentiation (LTP) mechanisms that contribute to the cognitive deficits found in DS. The purpose of this study was to evaluate the effect of Dyrk1A overexpression on the behavioral and cognitive alterations in the Ts65Dn (TS) mouse model, which is the most commonly utilized mouse model of DS, as well as on several neuromorphological and electrophysiological properties proposed to underlie these deficits. In this study, we analyzed the phenotypic differences in the progeny obtained from crosses of TS females and heterozygous Dyrk1A (+/2) male mice. Our results revealed that normalization of the Dyrk1A copy number in TS mice improved working and reference memory based on the Morris water maze and contextual conditioning based on the fear conditioning test and rescued hippocampal LTP. Concomitant with these functional improvements, normalization of the Dyrk1A expression level in TS mice restored the proliferation and differentiation of hippocampal cells in the adult dentate gyrus (DG) and the density of GABAergic and glutamatergic synapse markers in the molecular layer of the hippocampus. However, normalization of the Dyrk1A gene dosage did not affect other structural (e.g., the density of mature hippocampal granule cells, the DG volume and the subgranular zone area) or behavioral (i.e., hyperactivity/attention) alterations found in the TS mouse. These results suggest that Dyrk1A overexpression is involved in some of the cognitive, electrophysiological and neuromorphological alterations, but not in the structural alterations found in DS, and suggest that pharmacological strategies targeting this gene may improve the treatment of DS-associated learning disabilities. © 2014 García-Cerro et al. Source
Vidal-Laliena M.,University of Barcelona |
Gallastegui E.,University of Barcelona |
Mateo F.,CSIC - Institute of Refrigeration |
Martinez-Balbas M.,Barcelona Institute of Molecular Biology |
And 2 more authors.
Journal of Biological Chemistry | Year: 2013
Background: Cyclin A is a regulatory subunit of cyclin-dependent kinases that are key enzymes in the regulation of cell cycle progression. Results: Histone deacetylase 3 (HDAC3) regulates cyclin A deacetylation. Conclusion: HDAC3 regulates cyclin A stability by modulating cyclin A acetylation. Significance: HDAC3 regulates cell cycle progression by controlling cyclin A levels © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Source
Celia-Terrassa T.,Barcelona Institute of Molecular Biology |
Meca-Cortes O.,Barcelona Institute of Molecular Biology |
Mateo F.,Barcelona Institute of Molecular Biology |
De Paz A.M.,Barcelona Institute of Molecular Biology |
And 22 more authors.
Journal of Clinical Investigation | Year: 2012
Malignant progression in cancer requires populations of tumor-initiating cells (TICs) endowed with unlimited self renewal, survival under stress, and establishment of distant metastases. Additionally, the acquisition of invasive properties driven by epithelial-mesenchymal transition (EMT) is critical for the evolution of neoplastic cells into fully metastatic populations. Here, we characterize 2 human cellular models derived from prostate and bladder cancer cell lines to better understand the relationship between TIC and EMT programs in local invasiveness and distant metastasis. The model tumor subpopulations that expressed a strong epithelial gene program were enriched in highly metastatic TICs, while a second subpopulation with stable mesenchymal traits was impoverished in TICs. Constitutive overexpression of the transcription factor Snai1 in the epithelial/ TIC-enriched populations engaged a mesenchymal gene program and suppressed their self renewal and metastatic phenotypes. Conversely, knockdown of EMT factors in the mesenchymal-like prostate cancer cell subpopulation caused a gain in epithelial features and properties of TICs. Both tumor cell subpopulations cooperated so that the nonmetastatic mesenchymal-like prostate cancer subpopulation enhanced the in vitro invasiveness of the metastatic epithelial subpopulation and, in vivo, promoted the escape of the latter from primary implantation sites and accelerated their metastatic colonization. Our models provide new insights into how dynamic interactions among epithelial, self-renewal, and mesenchymal gene programs determine the plasticity of epithelial TICs. Source