Spanish National Cancer Center

Madrid, Spain

Spanish National Cancer Center

Madrid, Spain
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Carnero A.,Spanish National Cancer Center | Carnero A.,Institute Biomedicina Of Seville
Current Pharmaceutical Design | Year: 2010

PKB/AKT constitutes an important pathway that regulates the signaling of multiple essential biological processes. PTEN is a dual protein/lipid phosphatase whose main substrate is phosphatidyl-inositol,3,4,5 triphosphate (PIP3), the product of PI3K. Increases in PIP3 result in the recruitment of PDK1 and AKT to the membrane where they are activated. Furthermore, PI3K can be activated by direct binding to oncogenic Ras proteins. Many components of this pathway have been described as genetically altered in cancer. PTEN activity is lost by mutations, deletions or promoter methylation at high frequency in many primary and metastatic human cancers, and some germline mutations of PTEN are found in several familial cancer predisposition syndromes. Activating mutations of PI3K occur in human tumors and confer tumorigenic properties to cells in culture. Taken together, this evidence indicates that the AKT pathway is a promising potential target for cancer chemotherapy. Indeed, many companies and academic laboratories have initiated a variety of approaches to inhibit the pathway at different points. Essentially, PI3Ks, PDK1, AKT and mTOR are heavily targeted for therapy in different ways. These proteins are kinases, which are very "druggable" targets a priori, and, according to the "addiction hypothesis", cancer cells with the activated pathway will be more dependent on its activity for their survival. © 2010 Bentham Science Publishers Ltd.


Petrova E.,Spanish National Cancer Center | Soldini D.,University of Zürich | Moreno E.,Spanish National Cancer Center | Moreno E.,University of Bern
Communicative and Integrative Biology | Year: 2011

In Drosophila, the elimination of viable but suboptimal cells is mediated by cell competition, ensuring that these cells do not accumulate during development. In addition, certain genes such as the Drosophila homologue of human c-myc (dmyc) are able to transform cells into supercompetitors, which eliminate neighboring wild-type cells by apoptosis and overproliferate leaving total cell numbers unchanged. We have recently identified Drosophila SPARC as an early marker transcriptionally upregulated in loser cells that provides a transient protection by inhibiting caspase activation in outcompeted cells. Here, we explore whether the expression of SPARC in human tumors is consistent with a role for cell competition during human cancer and find that, consistent with the existence of competitive interactions between cancer and normal cells, SPARC is upregulated at the tumor-host boundaries in several types of human cancer. © 2011 Landes Bioscience.


Portela M.,Spanish National Cancer Center | Casas-Tinto S.,Spanish National Cancer Center | Rhiner C.,Spanish National Cancer Center | Rhiner C.,University of Bern | And 5 more authors.
Developmental Cell | Year: 2010

During development and aging, animals suffer insults that modify the fitness of individual cells. In Drosophila, the elimination of viable but suboptimal cells is mediated by cell competition, ensuring that these cells do not accumulate during development. In addition, certain genes such as the Drosophila homolog of human c-myc (dmyc) are able to transform cells into supercompetitors, which eliminate neighboring wild-type cells by apoptosis and overproliferate, leaving total cell numbers unchanged. Here we have identified Drosophila Sparc as an early marker transcriptionally upregulated in loser cells that provides a transient protection by inhibiting Caspase activation in outcompeted cells. Overall, we describe the unexpected existence of a physiological mechanism that counteracts cell competition during development. © 2010 Elsevier Inc.


Lolo F.-N.,Spanish National Cancer Center | Casas-Tinto S.,Spanish National Cancer Center | Moreno E.,University of Bern | Moreno E.,Spanish National Cancer Center
Cell Reports | Year: 2012

Cell competition is a mechanism that eliminates slow dividing cells from a growing population. It is believed that the genes wasp, psr, and draper are active in the cells that win the competition (" winner cells" ) and that they are essential in the winner cells for the induction of apoptosis and for the elimination of the " loser cells." Here, we show that lack of those genes in winner cells appears to be dispensable for cell-competition-induced apoptosis and during dmyc-induced supercompetition. Moreover, winner clones do not need those genes in order to preserve their growth advantage. Finally, we find that most of the clearance of the apoptotic debris is not performed by winners but by recruited hemocytes, which are required for the removal of the apoptotic corpses at the very end. Therefore, engulfment is a consequence-not a cause-of loser cells' death. Cell competition is a mechanism that removes viable but suboptimal cells from a growing population. It is believed that the genes wasp, psr, and draper are active in the cells that win the competition. Lolo, Tintó, and Moreno found that these genes are dispensable for cell-competition-induced apoptosis and winner cell overgrowth. Therefore, engulfment is a consequence-not a cause-of loser cells' death and is instead accomplished by recruited hemocytes. © 2012 The Authors.


Cuadrado A.,Spanish National Cancer Center | Nebreda A.R.,Spanish National Cancer Center
Biochemical Journal | Year: 2010

The p38 MAPK (mitogen-activated protein kinase) signalling pathway allows cells to interpret a wide range of external signals and respond appropriately by generating a plethora of different biological effects. The diversity and specificity in cellular outcomes is achieved with an apparently simple linear architecture of the pathway, consisting of a core of three protein kinases acting sequentially. In the present review, we dissect the molecular mechanisms underlying p38 MAPK functions, with special emphasis on the activation and regulation of the core kinases, the interplay with other signalling pathways and the nature of p38 MAPK substrates as a source of functional diversity. Finally, we discuss how genetic mouse models are facilitating the identification of physiological functions for p38 MAPKs, which may impinge on their eventual use as therapeutic targets. © The Authors.


Luther J.,Friedrich - Alexander - University, Erlangen - Nuremberg | Ubieta K.,Friedrich - Alexander - University, Erlangen - Nuremberg | Hannemann N.,Friedrich - Alexander - University, Erlangen - Nuremberg | Jimenez M.,Spanish National Cancer Center | And 5 more authors.
Cell Death and Differentiation | Year: 2014

Adipocyte cell number is a crucial factor for controlling of body weight and metabolic function. The regulation of adipocyte numbers in the adult organism is not fully understood but is considered to depend on the homeostasis of cell differentiation and apoptosis. Herein, we show that targeted deletion of the activator protein (AP-1)-related transcription factor Fra-2 in adipocytes in vivo (Fra-2Δadip mice) induces a high-turnover phenotype with increased differentiation and apoptosis of adipocytes, leading to a decrease in body weight and fat pad mass. Importantly, adipocyte cell numbers were significantly reduced in Fra-2 Δadip mice. At the molecular level, Fra-2 directly binds to the PPARγ2 promoter and represses PPARγ2 expression. Deletion of Fra-2 leads to increased PPARγ2 expression and adipocyte differentiation as well as increased adipocyte apoptosis through upregulation of hypoxia-inducible factors (HIFs). These findings suggest that Fra-2 is an important checkpoint to control adipocyte turnover. Therefore, inhibition of Fra-2 may emerge as a useful strategy to increase adipocyte turnover and to reduce adipocyte numbers and fat mass in the body. © 2014 Macmillan Publishers Limited All rights reserved.


Rhiner C.,Spanish National Cancer Center | Lopez-Gay J.M.,Spanish National Cancer Center | Soldini D.,Spanish National Cancer Center | Casas-Tinto S.,Spanish National Cancer Center | And 3 more authors.
Developmental Cell | Year: 2010

Cell competition promotes the elimination of weaker cells from a growing population. Here we investigate how cells of Drosophila wing imaginal discs distinguish "winners" from "losers" during cell competition. Using genomic and functional assays, we have identified several factors implicated in the process, including Flower (Fwe), a cell membrane protein conserved in multicellular animals. Our results suggest that Fwe is a component of the cell competition response that is required and sufficient to label cells as "winners" or "losers." In Drosophila, the fwe locus produces three isoforms, fweubi, fweLose-A, and fweLose-B. Basal levels of fweubi are constantly produced. During competition, the fweLose isoforms are upregulated in prospective loser cells. Cell-cell comparison of relative fweLose and fweubi levels ultimately determines which cell undergoes apoptosis. This "extracellular code" may constitute an ancient mechanism to terminate competitive conflicts among cells. © 2010 Elsevier Inc.


Cuadrado A.,Spanish National Cancer Center | Corrado N.,Spanish National Cancer Center | Perdiguero E.,University Pompeu Fabra | Lafarga V.,Spanish National Cancer Center | And 2 more authors.
EMBO Journal | Year: 2010

The chromatin-remodelling complex SNF2-related CBP activator protein (SRCAP) regulates chromatin structure in yeast by modulating the exchange of histone H2A for the H2A.Z variant. Here, we have investigated the contribution of H2A.Z-mediated chromatin remodelling to mammalian cell differentiation reprogramming. We show that the SRCAP subunit named ZNHIT1 or p18 Hamlet, which is a substrate of p38 MAPK, is recruited to the myogenin promoter at the onset of muscle differentiation, in a p38 MAPK-dependent manner. We also show that p18 Hamlet is required for H2A.Z accumulation into this genomic region and for subsequent muscle gene transcriptional activation. Accordingly, downregulation of several subunits or the SRCAP complex impairs muscle gene expression. These results identify SRCAP/H2A.Z-mediated chromatin remodelling as a key early event in muscle differentiation-specific gene expression. We also propose a mechanism by which p38 MAPK-mediated signals are converted into chromatin structural changes, thereby facilitating transcriptional activation during mammalian cell differentiation. © 2010 European Molecular Biology Organization.


Rueda O.M.,Spanish National Cancer Center | Rueda O.M.,Cancer Research UK | Diaz-Uriarte R.,Spanish National Cancer Center
Current Bioinformatics | Year: 2010

Copy number alterations (CNA) in genomic DNA are linked to a variety of human diseases. Although many methods have been developed to analyze data from a single subject, disease-critical genes are more likely to be found in regions that are common or recurrent among diseased subjects. Unfortunately, finding recurrent CNA regions remains a challenge. We review existing methods for the identification of recurrent CNA regions. Methods differ in their working definition of "recurrent region", the type of input data, the statistical and computational methods used to identify recurrence, and the biological considerations they incorporate (which play a role in the identification of "interesting" regions and in the details of null models used to assess statistical significance). Very few approaches use and/or return probabilities, and code is not easily available for several methods. We emphasize that, when analyzing data from complex diseases with significant among-subject heterogeneity, methods should be able to identify CNAs that affect only a subset of subjects. We suggest that finding recurrent CNAs would benefit from clearly specifying the types of pattern to be detected and the intended usage of the regions found (CNA association with disease, CNA effects on gene expression, clustering of subjects). We finish with suggestions for further methodological research. © 2010 Bentham Science Publishers Ltd.


Ruiz E.J.,Spanish National Cancer Center | Vilar M.,Spanish National Cancer Center | Nebreda A.R.,Spanish National Cancer Center
Current Biology | Year: 2010

Activation of CDK1 is essential for M-phase entry both in mitosis and meiosis. G2-arrested oocytes contain a pool of CDK1/cyclin B complexes that are maintained inactive because of the phosphorylation of CDK1 on Thr14 and Tyr15 by the Wee1 family protein kinase Myt1, whose inhibition suffices to induce meiosis I entry [1-5]. CDK1/XRINGO and p90Rsk can both phosphorylate and downregulate Myt1 activity in vitro [6, 7]. Here we identify five p90Rsk phosphorylation sites on Myt1 that are different from the CDK1/XRINGO sites, and we show how both kinases synergize during oocyte maturation to inhibit Myt1, ensuring meiotic progression. We found that phosphorylation of Myt1 by CDK1/XRINGO early during oocyte maturation not only downregulates Myt1 kinase activity but also facilitates the recruitment of p90Rsk and further phosphorylation of Myt1. Mutation of the five p90Rsk residues to alanine impairs Myt1 hyperphosphorylation during oocyte maturation and makes Myt1 resistant to the inhibition by p90Rsk. Importantly, Myt1 phosphorylated by p90Rsk does not interact with CDK1/cyclin B, ensuring that the inhibitory phosphorylations of CDK1 cannot take place after meiosis I entry and contributing to the all-or-none meiotic response. © 2010 Elsevier Ltd. All rights reserved.

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