Institute Hospital del Mar dInvestigacions Mediques IMIM

Barcelona, Spain

Institute Hospital del Mar dInvestigacions Mediques IMIM

Barcelona, Spain
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Dunach M.,Autonomous University of Barcelona | Del Valle-Perez B.,Autonomous University of Barcelona | Garcia de Herreros A.,Institute Hospital Del Mar Dinvestigacions Mediques Imim | Garcia de Herreros A.,University Pompeu Fabra
Critical Reviews in Biochemistry and Molecular Biology | Year: 2017

Canonical Wnt signaling controls β-catenin protein stabilization, its translocation to the nucleus and the activation of β-catenin/Tcf-4–dependent transcription. In this review, we revise and discuss the recent results describing actions of p120-catenin in different phases of this pathway. More specifically, we comment its involvement in four different steps: (i) the very early activation of CK1ɛ, essential for Dvl-2 binding to the Wnt receptor complex; (ii) the internalization of GSK3 and Axin into multivesicular bodies, necessary for a complete stabilization of β-catenin; (iii) the activation of Rac1 small GTPase, required for β-catenin translocation to the nucleus; and (iv) the release of the inhibitory action caused by Kaiso transcriptional repressor. We integrate these new results with the previously known action of other elements in this pathway, giving a particular relevance to the responses of the Wnt pathway not required for β-catenin stabilization but for β-catenin transcriptional activity. Moreover, we discuss the possible future implications, suggesting that the two cellular compartments where β-catenin is localized, thus, the adherens junction complex and the Wnt signalosome, are more physically connected that previously thought. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

Johnson R.,Center for Genomic Regulation | Johnson R.,University Pompeu Fabra | Johnson R.,Institute Hospital del Mar dInvestigacions Mediques IMIM | Guigo R.,Center for Genomic Regulation | And 2 more authors.
RNA | Year: 2014

Our genome contains tens of thousands of long noncoding RNAs (lncRNAs), many of which are likely to have genetic regulatory functions. It has been proposed that lncRNA are organized into combinations of discrete functional domains, but the nature of these and their identification remain elusive. One class of sequence elements that is enriched in lncRNA is represented by transposable elements (TEs), repetitive mobile genetic sequences that have contributed widely to genome evolution through a process termed exaptation. Here, we link these two concepts by proposing that exonic TEs act as RNA domains that are essential for lncRNA function. We term such elements Repeat Insertion Domains of LncRNAs (RIDLs). A growing number of RIDLs have been experimentally defined, where TE-derived fragments of lncRNA act as RNA-, DNA-, and protein-binding domains. We propose that these reflect a more general phenomenon of exaptation during lncRNA evolution, where inserted TE sequences are repurposed as recognition sites for both protein and nucleic acids. We discuss a series of genomic screens that may be used in the future to systematically discover RIDLs. The RIDL hypothesis has the potential to explain how functional evolution can keep pace with the rapid gene evolution observed in lncRNA. More practically, TE maps may in the future be used to predict lncRNA function. © 2014 Johnson and Guigó.

Benito B.,Hospital Del Mar | Benito B.,Institute Hospital Del Mar dInvestigacions Mediques IMIM | Josephson M.E.,Beth Israel Deaconess Medical Center
Revista Espanola de Cardiologia | Year: 2012

Ventricular arrhythmias are important contributors to morbidity and mortality in patients with coronary artery disease. Ventricular fibrillation accounts for the majority of deaths occurring in the acute phase of ischemia, whereas sustained, monomorphic ventricular tachycardia due to reentry generated in the scar tissue develops most often in the setting of healed myocardial infarction, especially in patients with lower left ventricular ejection fraction. Despite determinant advances in population education and myocardial infarction management, the ventricular tachycardia risk in the overall population with coronary artery disease continues to be a major problem in clinical practice. The initial evaluation of a patient presenting with ventricular tachycardia requires a 12-lead electrocardiogram, which can be helpful to confirm the diagnosis, suggest the presence of potential underlying heart disease, and identify the location of the ventricular tachycardia circuit. An invasive electrophysiologic study is usually crucial to determine the mechanism of the arrhythmia once induced and to provide guidance for ablation. The approach for ventricular tachycardia ablation depends on several factors, including inducibility, sustainability, and clinical tolerance of ventricular tachycardia. The paper also reviews other therapeutic options for patients with ventricular tachycardia associated with coronary artery disease, including antiarrhythmic drug therapy, surgical ablation, and current implantable cardioverter-defibrillator indications. ©2012 Sociedad Espanola de Cardiolog?a. Publicado por Elsevier Espana, S.L. Todos los derechos reservados.

Millanes-Romero A.,Institute Hospital del Mar dInvestigacions Mediques IMIM | Herranz N.,Imperial College London | Perrera V.,Max Planck Institute of Immunobiology and Epigenetics | Iturbide A.,Institute Hospital del Mar dInvestigacions Mediques IMIM | And 6 more authors.
Molecular Cell | Year: 2013

Although heterochromatin is enriched with repressive traits, it is also actively transcribed, giving rise to large amounts of noncoding RNAs. Although these RNAs are responsible for the formation and maintenance of heterochromatin, little is known about how their transcription is regulated. Here, we show that the Snail1 transcription factor represses mouse pericentromeric transcription, acting through the H3K4 deaminase LOXL2. Since Snail1 plays a key role in the epithelial-to-mesenchymal transition (EMT), we analyzed the regulation of heterochromatin transcription in this process. At the onset of EMT, one of the major structural heterochromatin proteins, HP1α, is transiently released from heterochromatin foci in a Snail1/LOXL2-dependent manner, concomitantly with a downregulation of major satellite transcription. Moreover, preventing the downregulation of major satellite transcripts compromised the migratory and invasive behavior of mesenchymal cells. We propose that Snail1 regulates heterochromatin transcription through LOXL2, thus creating the favorable transcriptional state necessary for completing EMT. © 2013 Elsevier Inc.

Segura J.,Institute Hospital Del Mar dInvestigacions Mediques IMIM | Segura J.,University Pompeu Fabra | Lundby C.,University of Zürich | Lundby C.,Gothenburg University
British Journal of Sports Medicine | Year: 2014

The collection of blood, its storage as red blood cell (RBC) concentrates and its reinjection is prohibited; until now, the practice cannot be reliably detected. A recent innovation-the haematological module of the athlete's biological passport-can provide authorities with indications towards autologous blood transfusion. In situations where a given athlete has been exposed to altitude, heat stress, sickness, etc, additional evidence may be needed to establish beyond any reasonable doubt that a blood transfusion may actually have occurred. Additional evidence may be obtained from at least three different approaches using parameters related to blood and urine matrices.Genomics applied to mRNA or miRNA is one of the most promising analytical tools. Proteomics of changes associated with RBC membranes may reveal the presence of cells stored for some time, as can an abnormal pattern of size distribution of aged cells. In urine, high concentrations of metabolites of plasticisers originating from the blood storing bags strongly suggest a recent blood transfusion. We emphasise the usefulness of simultaneously obtaining and then analysing blood and urine for complementary evidence of autologous blood transfusion ('blood doping').

Vinas-Castells R.,Institute Hospital Del Mar dInvestigacions Mediques IMIM | Frias A.,Institute Hospital Del Mar dInvestigacions Mediques IMIM | Frias A.,University Pompeu Fabra | Robles-Lanuza E.,Institute Hospital Del Mar dInvestigacions Mediques IMIM | And 6 more authors.
Nucleic Acids Research | Year: 2014

The zinc finger transcription factor Snail1 regulates epithelial to mesenchymal transition, repressing epithelial markers and activating mesenchymal genes. Snail1 is an extremely labile protein degraded by the cytoplasmic ubiquitin-ligases β-TrCP1/FBXW1 and Ppa/FBXL14. Using a short hairpin RNA screening, we have identified FBXL5 as a novel Snail1 ubiquitin ligase. FBXL5 is located in the nucleus where it interacts with Snail1 promoting its polyubiquitination and affecting Snail1 protein stability and function by impairing DNA binding. Snail1 downregulation by FBXL5 is prevented by Lats2, a protein kinase that phosphorylates Snail1 precluding its nuclear export but not its polyubiquitination. Actually, although polyubiquitination by FBXL5 takes place in the nucleus, Snail1 is degraded in the cytosol. Finally, FBXL5 is highly sensitive to stress conditions and is downregulated by iron depletion and γ-irradiation, explaining Snail1 stabilization in these conditions. These results characterize a novel nuclear ubiquitin ligase controlling Snail1 protein stability and provide the molecular basis for understanding how radiotherapy upregulates the epithelial to mesenchymal transition-inducer Snail1. © 2013 The Author(s).

Espinosa L.,Institute Hospital Del Mar dInvestigacions Mediques IMIM | Margalef P.,Institute Hospital Del Mar dInvestigacions Mediques IMIM | Bigas A.,Institute Hospital Del Mar dInvestigacions Mediques IMIM
Oncogene | Year: 2015

NF-κB pathway exerts an essential function in the regulation of the immune response, which has been the nucleus of numerous studies for the past 25 years. Both activation of the pathway and termination of the NF-κB response are tightly regulated events, which is essential to prevent exacerbated inflammatory responses. Thus, alterations in NF-κB regulatory elements might result in tissue damage and cancer in different systems. In addition, several of the proteins involved in NF-κB regulation display additional, and much less studied, functions that connect with specific NF-κB-unrelated pathways. Many of these pathways are in turn regulators of particular physiologic and/or pathologic responses. Which are the principal non-conventional functions that have been identified for specific NF-κB elements, how they connect with other signaling pathways and what is their potential impact on cancer is the focus of this review. © 2015 Macmillan Publishers Limited All rights reserved.

Vinyoles M.,Autonomous University of Barcelona | DelValle-Perez B.,Autonomous University of Barcelona | Curto J.,Autonomous University of Barcelona | Vinas-Castells R.,Institute Hospital del Mar dInvestigacions Mediques IMIM | And 4 more authors.
Molecular Cell | Year: 2014

The Wnt canonical ligands elicit the activation ofβ-catenin transcriptional activity, a response dependent on, but not limited to, β-catenin stabilization through the inhibition of GSK3 activity. Two mechanisms have been proposed for this inhibition, one dependent on the binding and subsequent block of GSK3 to LRP5/6 Wnt coreceptor and another one on its sequestration into multivesicular bodies (MVBs). Here we report that internalization ofthe GSK3-containing Wnt-signalosome complex into MVBs is dependent on the dissociation of p120-catenin/cadherin from this complex. Disruption of cadherin-LRP5/6 interaction is controlled by cadherin phosphorylation and requires the previous separation of p120-catenin; thus, p120-catenin and cadherin mutants unable to dissociate from the complex block GSK3 sequestration into MVBs.These mutants substantially inhibit, but donot completely prevent, the β-catenin upregulationcaused by Wnt3a. These results, besides elucidating how GSK3 is sequestered into MVBs, support this mechanism as cause of β-catenin stabilization by Wnt. © 2014 Elsevier Inc.

Gekas C.,Institute Hospital Del Mar Dinvestigacions Mediques Imim
Leukemia | Year: 2016

Notch activation is instrumental in the development of most T-cell acute lymphoblastic leukemia (T-ALL) cases, yet Notch mutations alone are not sufficient to recapitulate the full human disease in animal models. We here found that Notch1 activation at the fetal liver (FL) stage expanded the hematopoietic progenitor population and conferred it transplantable leukemic-initiating capacity. However, leukemogenesis and leukemic-initiating cell capacity induced by Notch1 was critically dependent on the levels of β-Catenin in both FL and adult bone marrow contexts. In addition, inhibition of β-Catenin compromised survival and proliferation of human T-ALL cell lines carrying activated Notch1. By transcriptome analyses, we identified the MYC pathway as a crucial element downstream of β-Catenin in these T-ALL cells and demonstrate that the MYC 3′ enhancer required β-Catenin and Notch1 recruitment to induce transcription. Finally, PKF115-584 treatment prevented and partially reverted leukemogenesis induced by active Notch1.Leukemia advance online publication, 17 May 2016; doi:10.1038/leu.2016.106. © 2016 Macmillan Publishers Limited

Bigas A.,Institute Hospital del Mar dInvestigacions Mediques IMIM | Guiu J.,Institute Hospital del Mar dInvestigacions Mediques IMIM | Gama-Norton L.,Institute Hospital del Mar dInvestigacions Mediques IMIM
Blood Cells, Molecules, and Diseases | Year: 2013

Hematopoietic stem cells (HSC), which reside in the marrow of adult mammals and sustain hematopoiesis for the lifetime of the organism, are specified and generated during embryonic development. We are just beginning to understand how HSC develop from more primitive cells and the complexity of the signaling pathways involved. In this work, we review the role of two crucial pathways, Notch and Wnt, in the specification and development of HSC and their nascent microenvironment, the arterial vessels. © 2013 Elsevier Inc.

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