Institute Investigaciones Biomedicas Alberto Sols

Madrid, Spain

Institute Investigaciones Biomedicas Alberto Sols

Madrid, Spain
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Puyol M.,Massachusetts Institute of Technology | Martin A.,Institute Investigaciones Biomedicas Alberto Sols | Dubus P.,University of Bordeaux Segalen | Khan G.,United Arab Emirates University
Cancer Cell | Year: 2010

We have unveiled a synthetic lethal interaction between K-Ras oncogenes and Cdk4 in a mouse tumor model that closely recapitulates human non-small cell lung carcinoma (NSCLC). Ablation of Cdk4, but not Cdk2 or Cdk6, induces an immediate senescence response only in lung cells that express an endogenous K-Ras oncogene. No such response occurs in lungs expressing a single Cdk4 allele or in other K-Ras-expressing tissues. More importantly, targeting Cdk4 alleles in advanced tumors detectable by computed tomography scanning also induces senescence and prevents tumor progression. These observations suggest that robust and selective pharmacological inhibition of Cdk4 may provide therapeutic benefit for NSCLC patients carrying K-RAS oncogenes. © 2010 Elsevier Inc.

Munoz-Espin D.,Tumor Suppression Group | Canamero M.,Histopathology Unit | Maraver A.,Tumor Suppression Group | Gomez-Lopez G.,Bioinformatics Unit | And 12 more authors.
Cell | Year: 2013

Cellular senescence disables proliferation in damaged cells, and it is relevant for cancer and aging. Here, we show that senescence occurs during mammalian embryonic development at multiple locations, including the mesonephros and the endolymphatic sac of the inner ear, which we have analyzed in detail. Mechanistically, senescence in both structures is strictly dependent on p21, but independent of DNA damage, p53, or other cell-cycle inhibitors, and it is regulated by the TGF-β/SMAD and PI3K/FOXO pathways. Developmentally programmed senescence is followed by macrophage infiltration, clearance of senescent cells, and tissue remodeling. Loss of senescence due to the absence of p21 is partially compensated by apoptosis but still results in detectable developmental abnormalities. Importantly, the mesonephros and endolymphatic sac of human embryos also show evidence of senescence. We conclude that the role of developmentally programmed senescence is to promote tissue remodeling and propose that this is the evolutionary origin of damage-induced senescence. © 2013 Elsevier Inc.

Casado-Vela J.,CSIC - National Center for Biotechnology | Lacal J.C.,Institute Investigaciones Biomedicas Alberto Sols | Elortza F.,CIC Biomagune
Proteomics | Year: 2013

Three main molecular mechanisms are considered to contribute expanding the repertoire and diversity of proteins present in living organisms: first, at DNA level (gene polymorphisms and single nucleotide polymorphisms); second, at messenger RNA (pre-mRNA and mRNA) level including alternative splicing (also termed differential splicing or cis-splicing); finally, at the protein level mainly driven through PTM and specific proteolytic cleavages. Chimeric mRNAs constitute an alternative source of protein diversity, which can be generated either by chromosomal translocations or by trans-splicing events. The occurrence of chimeric mRNAs and proteins is a frequent event in cells from the immune system and cancer cells, mainly as a consequence of gene rearrangements. Recent reports support that chimeric proteins may also be expressed at low levels under normal physiological circumstances, thus, representing a novel source of protein diversity. Notably, recent publications demonstrate that chimeric protein products can be successfully identified through bottom-up proteomic analyses. Several questions remain unsolved, such as the physiological role and impact of such chimeric proteins or the potential occurrence of chimeric proteins in higher eukaryotic organisms different from humans. The occurrence of chimeric proteins certainly seems to be another unforeseen source of complexity for the proteome. It may be a process to take in mind not only when performing bottom-up proteomic analyses in cancer studies but also in general bottom-up proteomics experiments. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Flores C.-L.,Institute Investigaciones Biomedicas Alberto Sols | Gancedo C.,Institute Investigaciones Biomedicas Alberto Sols
IUBMB Life | Year: 2011

This review considers the use of yeasts to study protein moonlighting functions. The cases discussed highlight the possibilities offered by the well-developed yeast genetics for the study of moonlighting mechanisms. The possibility to generate sets of mutants encoding different protein variants has allowed in some cases to map the regions that participate in the moonlighting function. We discuss cases of enzymes that moonlight in such different activities as control of transcription, assembly of multimeric proteins, stabilization of mitochondrial DNA or biosynthesis of CoA. The moonlighting role of an enzyme and its metabolic function seems to have evolved independently as indicated by the finding that a protein may moonlight in a yeast species but not in others. Yeasts may open ways to study possible evolutionary relationships among moonlighting proteins. © 2011 IUBMB.

Cano A.,Institute Investigaciones Biomedicas Alberto Sols | Santamaria P.G.,Institute Investigaciones Biomedicas Alberto Sols | Moreno-Bueno G.,Institute Investigaciones Biomedicas Alberto Sols
Future Oncology | Year: 2012

Several members of the lysyl oxidase family have recently emerged as important regulators of tumor progression. Among them, LOXL2 has been shown to be involved in tumor progression and metastasis of several tumor types, including breast carcinomas. Secreted LOXL2 participates in the remodeling of the extracellular matrix of the tumor microenvironment, in a similar fashion to prototypical lysyl oxidase. In addition, new intracellular functions of LOXL2 have been described, such as its involvement in the regulation of the epithelial-to-mesenchymal transition, epithelial cell polarity and differentiation mediated by transcriptional repression mechanisms. Importantly, intracellular (perinuclear) expression of LOXL2 is associated with poor prognosis and distant metastasis of specific tumor types, such as larynx squamous cell carcinoma and basal breast carcinomas. These recent findings open new avenues for the therapeutic utility of LOXL2. © 2012 Future Medicine Ltd.

Gancedo C.,Institute Investigaciones Biomedicas Alberto Sols | Flores C.-L.,Institute Investigaciones Biomedicas Alberto Sols | Gancedo J.M.,Institute Investigaciones Biomedicas Alberto Sols
Microbiology and Molecular Biology Reviews | Year: 2016

Moonlighting proteins are multifunctional proteins that participate in unrelated biological processes and that are not the result of gene fusion. A certain number of these proteins have been characterized in yeasts, and the easy genetic manipulation of these microorganisms has been useful for a thorough analysis of some cases of moonlighting. As the awareness of the moonlighting phenomenon has increased, a growing number of these proteins are being uncovered. In this review, we present a crop of newly identified moonlighting proteins from yeasts and discuss the experimental evidence that qualifies them to be classified as such. The variety of moonlighting functions encompassed by the proteins considered extends from control of transcription to DNA repair or binding to plasminogen. We also discuss several questions pertaining to the moonlighting condition in general. The cases presented show that yeasts are important organisms to be used as tools to understand different aspects of moonlighting proteins. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Alvarez-Castelao B.,Institute Investigaciones Biomedicas Alberto Sols | Goethals M.,Ghent University | Vandekerckhove J.,Ghent University | Castano J.G.,Institute Investigaciones Biomedicas Alberto Sols | Castano J.G.,Ghent University
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2014

Alpha-synuclein is a small protein implicated in the pathophysiology of Parkinson's disease (PD). We have investigated the mechanism of cleavage of alpha-synuclein by the 20S proteasome. Alpha-synuclein interacts with the C8 (α7) subunit of the proteasome. The N-terminal part of alpha-synuclein (amino acids 1-60) is essential for its proteasomal degradation and analysis of peptides released from proteasomal digestion allows concluding that initial cleavages occur within the N-terminal region of the molecule. Aggregated alpha-synucleins are also degraded by the proteasome with a reduced rate, likely due to Met oxidation. In fact, mild oxidation of alpha-synuclein with H2O2 resulted in the inhibition of its degradation by the proteasome, mainly due to oxidation of Met 1 and 5 of alpha-synuclein. The inhibition was reversed by treatment of the oxidized protein with methionine sulfoxide reductases (MsrA plus MsrB). Similarly, treatment with H2O2 of N2A cells transfected with alpha-synuclein resulted in the inhibition of its degradation that was also reverted by co-transfection of MsrA plus MsrB. These results clearly indicate that oxidative stress, a common feature of PD and other synucleinopathies, promotes a RedOx change in the proteostasis of alpha-synuclein due to Met oxidation and reduced proteasomal degradation; compromised reversion of those oxidative changes would result in the accumulation of oxidative damaged alpha-synuclein likely contributing to the pathogenesis of PD. © 2013 Elsevier B.V.

Gancedo C.,Institute Investigaciones Biomedicas Alberto Sols | Flores C.-L.,Institute Investigaciones Biomedicas Alberto Sols | Gancedo J.M.,Institute Investigaciones Biomedicas Alberto Sols
Biochemical Society Transactions | Year: 2014

The present article addresses the possibilities offered by yeasts to study the problem of the evolution of moonlighting proteins. It focuses on data available on hexokinase from Saccharomyces cerevisiae that moonlights in catabolite repression and on galactokinase from Kluyveromyces lactis that moonlights controlling the induction of the GAL genes. Possible experimental approaches to studying the evolution of moonlighting hexose kinases are suggested. © 2014 Biochemical Society.

Calvo-Garrido J.,Institute Investigaciones Biomedicas Alberto Sols | Escalante R.,Institute Investigaciones Biomedicas Alberto Sols
Autophagy | Year: 2010

Ubiquitin-positive protein aggregates are a hallmark of many degenerative diseases. Their presence can be induced by dysfunction in protein degradation pathways such as proteasome and autophagy. We now report several lines of evidence suggesting a defect in autophagy in Dictyostelium cells lacking Vmp1 (vacuole membrane protein 1), an endoplasmic reticulum (eR)-resident protein involved in pathological processes such as cancer and pancreatitis. vmp1 - null cells are unable to survive starvation or undergo autophagic cell death under the appropriate inductive signals. Moreover, confocal studies using the autophagy marker Atg8 and previous transmission electron microscopy analysis showed defects in autophagosome formation. Although Vmp1 is localized in the eR, we found colocalization with Atg8 suggesting a contribution of both Vmp1 and eR in autophagosome biogenesis or maturation. Interestingly, vmp1 - mutant cells showed accumulation of huge ubiquitin-positive protein aggregates containing the autophagy marker GFP-Atg8 and the putative Dictyostelium p62 homologue as described in many degenerative human diseases. The analysis of other Dictyostelium autophagic mutants (atg1-, atg5-, atg6-, atg7- and atg8-) showed a correlation in the severity of their corresponding phenotypes and the presence of ubiquitin-positive protein aggregates suggesting that the deleterious effects associated with development of these aggregates might contribute to the complex phenotypes observed in autophagy deficient mutants. Our results suggest that Vmp1 is required for the clearance of these ubiquitinated protein aggregates through autophagy and highlight a potential role for Vmp1 in protein-aggregation diseases. © 2010 Landes Bioscience.

Fernandez-Velasco M.,Hospital Universitario La Paz | Gonzalez-Ramos S.,Institute Investigaciones Biomedicas Alberto Sols | Bosca L.,Institute Investigaciones Biomedicas Alberto Sols
Biochemical Journal | Year: 2014

Emerging evidence points to the involvement of specialized cells of the immune system as key drivers in the pathophysiology of cardiovascular diseases.Monocytes are an essential cell component of the innate immune system that rapidly mobilize from the bone marrow to wounded tissues where they differentiate into macrophages or dendritic cells and trigger an immune response. In the healthy heart a limited, but near-constant, number of resident macrophages have been detected; however, this number significantly increases during cardiac damage. Shortly after initial cardiac injury, e.g. myocardial infarction, a large number of macrophages harbouring a pro-inflammatory profile (M1) are rapidly recruited to the cardiac tissue, where they contribute to cardiac remodelling. After this initial period, resolution takes place in the wound, and the infiltrated macrophages display a predominant deactivation/pro-resolution profile (M2), promoting cardiac repair by mediating pro-fibrotic responses. In the present reviewwe focus on the role of the immune cells, particularly in the monocyte/macrophage population, in the progression of themajor cardiac pathologies myocardial infarction and atherosclerosis. © 2014 Biochemical Society.

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