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De Juan D.,Spanish National Cancer Research Center | Pazos F.,CSIC - National Center for Biotechnology | Valencia A.,Spanish National Cancer Research Center
Nature Reviews Genetics | Year: 2013

Co-evolution is a fundamental component of the theory of evolution and is essential for understanding the relationships between species in complex ecological networks. A wide range of co-evolution-inspired computational methods has been designed to predict molecular interactions, but it is only recently that important advances have been made. Breakthroughs in the handling of phylogenetic information and in disentangling indirect relationships have resulted in an improved capacity to predict interactions between proteins and contacts between different protein residues. Here, we review the main co-evolution-based computational approaches, their theoretical basis, potential applications and foreseeable developments. © 2013 Macmillan Publishers Limited. All rights reserved.


Domenech E.,Spanish National Cancer Research Center
PloS one | Year: 2012

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease without a well-defined genetic alteration responsible for the onset of the disease. Several lines of evidence coincide in identifying stimulatory and growth signals delivered by B-cell receptor (BCR), and co-receptors together with NFkB pathway, as being the driving force in B-cell survival in CLL. However, the molecular mechanism responsible for this activation has not been identified. Based on the hypothesis that BCR activation may depend on somatic mutations of the BCR and related pathways we have performed a complete mutational screening of 301 selected genes associated with BCR signaling and related pathways using massive parallel sequencing technology in 10 CLL cases. Four mutated genes in coding regions (KRAS, SMARCA2, NFKBIE and PRKD3) have been confirmed by capillary sequencing. In conclusion, this study identifies new genes mutated in CLL, all of them in cases with progressive disease, and demonstrates that next-generation sequencing technologies applied to selected genes or pathways of interest are powerful tools for identifying novel mutational changes.


Bakiri L.,Spanish National Cancer Research Center | Wagner E.F.,Spanish National Cancer Research Center
Molecular Oncology | Year: 2013

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer is the third leading cause of cancer-related cell death in human and the fifth in women worldwide. The incidence of HCC is increasing despite progress in identifying risk factors, understanding disease etiology and developing anti-viral strategies. Therapeutic options are limited and survival after diagnosis is poor. Therefore, better preventive, diagnostic and therapeutic tools are urgently needed, in particular given the increased contribution from systemic metabolic disease to HCC incidence worldwide. In the last three decades, technological advances have facilitated the generation of genetically engineered mouse models (GEMMs) to mimic the alterations frequently observed in human cancers or to conduct intervention studies and assess the relevance of candidate gene networks in tumor establishment, progression and maintenance. Because these studies allow molecular and cellular manipulations impossible to perform in patients, GEMMs have improved our understanding of this complex disease and represent a source of great potential for mechanism-based therapy development. In this review, we provide an overview of the current state of HCC modeling in the mouse, highlighting successes, current challenges and future opportunities. © 2013 Federation of European Biochemical Societies.


Ortega-Molina A.,Spanish National Cancer Research Center | Serrano M.,Spanish National Cancer Research Center
Trends in Endocrinology and Metabolism | Year: 2013

Recent reports on mice with systemic overexpression of the tumor-suppressor PTEN (phosphatase and tensin homolog) have expanded our understanding of its physiological functions. Pten transgenic mice present increased energy expenditure, decreased adiposity, improved insulin sensitivity upon high-fat feeding or with aging, and extended lifespan. This has led to new mechanistic insights about the role of PTEN in metabolism. Interestingly, PTEN promotes oxidative phosphorylation and decreases glycolysis, thus preventing the metabolic reprogramming characteristic of cancer cells, which might be relevant to PTEN-mediated cancer protection. PTEN also upregulates UCP1 expression in brown adipocytes, which enhances their nutrient burning capacity and decreases adiposity and associated pathologies. The newly discovered effects of PTEN on metabolism open new avenues for exploration relevant to cancer, obesity, diabetes, and aging. © 2012 Elsevier Ltd.


Izarzugaza J.M.,Spanish National Cancer Research Center
BMC genomics | Year: 2012

Most of the many mutations described in human protein kinases are tolerated without significant disruption of the corresponding structures or molecular functions, while some of them have been associated to a variety of human diseases, including cancer. In the last decade, a plethora of computational methods to predict the effect of missense single-nucleotide variants (SNVs) have been developed. Still, current high-throughput sequencing efforts and the concomitant need for massive interpretation of protein sequence variants will demand for more efficient and/or accurate computational methods in the forthcoming years. We present KinMut, a support vector machine (SVM) approach, to identify pathogenic mutations in the protein kinase superfamily. KinMut relays on a combination of sequence-derived features that describe mutations at different levels: (1) Gene level: membership to a specific group in Kinbase and the annotation with GO terms; (2) Domain level: annotated PFAM domains; and (3) Residue level: physicochemical features of amino acids, specificity determining positions, and functional annotations from SwissProt and FireDB. The system has been trained with the set of 3492 human kinase mutations in UniProt for which experimental validation of their pathogenic or neutral character exists. In addition, we discuss the relative importance of these independent properties and their combination for the development of a kinase-specific predictor. Finally, we compare KinMut with other state-of-the-art prediction methods. Family-specific features appear among the most discriminative information sources, which allow us to produce accurate results in a reliable and very simple way with minimal supervision. Our study aims to broaden the knowledge on the mechanisms by which mutations in the human kinome contribute to disease with a particular focus in cancer. The classifier as well as further documentation is available at http://kinmut.bioinfo.cnio.es/.


Malumbres M.,Spanish National Cancer Research Center
Nature Reviews Molecular Cell Biology | Year: 2016

The roles of cyclins and their catalytic partners, the cyclin-dependent kinases (CDKs), as core components of the machinery that drives cell cycle progression are well established. Increasing evidence indicates that mammalian cyclins and CDKs also carry out important functions in other cellular processes, such as transcription, DNA damage repair, control of cell death, differentiation, the immune response and metabolism. Some of these non-canonical functions are performed by cyclins or CDKs, independently of their respective cell cycle partners, suggesting that there was a substantial divergence in the functions of these proteins during evolution. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Frenkel-Morgenstern M.,Spanish National Cancer Research Center | Valencia A.,Spanish National Cancer Research Center
Bioinformatics | Year: 2012

Motivation: Chimeric RNA transcripts are generated by different mechanisms including pre-mRNA trans-splicing, chromosomal translocations and/or gene fusions. It was shown recently that at least some of chimeric transcripts can be translated into functional chimeric proteins. Results: To gain a better understanding of the design principles underlying chimeric proteins, we have analyzed 7,424 chimeric RNAs from humans. We focused on the specific domains present in these proteins, comparing their permutations with those of known human proteins. Our method uses genomic alignments of the chimeras, identification of the gene-gene junction sites and prediction of the protein domains. We found that chimeras contain complete protein domains significantly more often than in random data sets. Specifically, we show that eight different types of domains are over-represented among all chimeras as well as in those chimeras confirmed by RNA-seq experiments. Moreover, we discovered that some chimeras potentially encode proteins with novel and unique domain combinations. Given the observed prevalence of entire protein domains in chimeras, we predict that certain putative chimeras that lack activation domains may actively compete with their parental proteins, thereby exerting dominant negative effects. More generally, the production of chimeric transcripts enables a combinatorial increase in the number of protein products available, which may disturb the function of parental genes and influence their protein-protein interaction network. © The Author(s) 2012. Published by Oxford University Press.


Malumbres M.,Spanish National Cancer Research Center | Perez De Castro I.,Spanish National Cancer Research Center
Expert Opinion on Therapeutic Targets | Year: 2014

Introduction: Aurora proteins are serine/threonine kinases with critical functions during mitosis. Aurora A, one of the members of this family, participates in crucial processes including mitotic entry, DNA damage checkpoint recovery and centrosome and spindle maturation. Aurora A is frequently overexpressed in human cancers and, when inhibited, impairs cell proliferation.Areas covered: Here, we review the preclinical studies that support the use of Aurora A inhibitors in antitumoral strategies. We also discuss past or current clinical trials using Aurora A inhibitors in multiple tumor types. We pay special attention to Alisertib, a potent and selective Aurora A inhibitor currently in Phase III.Expert opinion: The potential of Aurora A inhibitors in the treatment of cancer depends on many factors, mainly related with the molecular status of tumor cells. Yet, we still need to find proper biomarkers to select those patients that better react to Aurora A inhibitors. Furthermore, their effect could significantly improve when used in combination with other drugs. Although some clinical trials are already testing the cooperative effect of different antitumoral drugs, additional preclinical studies are necessary to establish the best combinations. Here, we discuss some possibilities that could be explored in future studies. © 2014 Informa UK, Ltd.


Blanco-Aparicio C.,Spanish National Cancer Research Center | Carnero A.,Institute Biomedicina Of Seville Ibis
Biochemical Pharmacology | Year: 2013

PIM proteins belong to a family of ser/thr kinases composed of 3 members, PIM1, PIM2 and PIM3, with greatly overlapping functions. PIM kinases are mainly responsible for cell cycle regulation, antiapoptotic activity and the homing and migration of receptor tyrosine kinases mediated via the JAK/STAT pathway. PIM kinases have been found to be upregulated in many hematological malignancies and solid tumors. Although these kinases have been described as weak oncogenes, they are heavily targeted for anticancer drug discovery. The present review summarizes the discoveries made to date regarding PIM kinases as driving oncogenes in the process of tumorigenesis and their validation as drug targets. © 2012 Elsevier Inc.


Serrano M.,Spanish National Cancer Research Center
EMBO Journal | Year: 2015

Cellular senescence is a response to stress that disables cell proliferation and orchestrates an inflammatory process that eliminates damaged cells. The first pro-senescence drugs for cancer treatment are now a clinical reality, but still few targets have been identified whose inactivation results in cancer cell senescence. Current work published in this issue of The EMBO Journal makes an important contribution to this area by discovering that pharmacological inhibition of the tyrosine phosphatase SHP2 blocks mouse mammary cancer through the induction of senescence (Lan et al,). Pharmacological inhibition of the tyrosine phosphatase SHP2 blocks mouse mammary cancer through the induction of senescence. © 2015 The Author.

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