CENTER FOR COOPERATIVE RESEARCH IN BIOSCIENCES
CENTER FOR COOPERATIVERESEARCH IN BIOSCIENCES
CIC bioGUNEPLAYS A STRONG ROLEIN ADVANCINGBIOMEDICAL RESEARCHAND TECHNOLOGICALINNOVATION INTHE BASQUE COUNTRY
The conviction that fundamentalbiomedical research and technological
innovation can be brought together drivesour work at the Center for CooperativeResearch in Biosciences, CIC bioGUNE.
We live in a time of discovery. Every year, newdiscoveries bring us closer to answering ofthe crucial questions about life; improvedunderstanding and treatment of disease havenever been so tantalizingly close. At the sametime, science and technology have becomeglobal and it is undeniable that scientificknowledge plays a fundamental role in thegeneration of wealth. However, not allcountries know how to obtain the bestsocioeconomic benefit from this commonknowledge (the so-called European paradox).The conviction that fundamental biomedical
research and technological innovation canbe brought together drives our work atthe Center for Cooperative Research inBiosciences, CIC bioGUNE.
CIC bioGUNE, a non-profit biomedical researchorganization founded in 2002 by the Departmentof Industry of the Basque Government, openedits research installations at the TechnologyPark of Bizkaia in January 2005. Since then,CIC bioGUNE has played a strong role inadvancing biomedical research andtechnological innovation in the Basque Country.
CIC bioGUNE invested over 35 million €in state-of-the-art research infrastructures,including genomics, gene silencing,proteomics, metabolomics, NMR, electronmicroscopy, x-ray diffraction, computer andanimal facilities, to support the researchactivities of its faculty and students.The Center commits every year more than5.5 million € for research and dedicates 450thousand € to PhD training. It employs 22faculty investigators, more than 85 postdocs,technicians and engineers, and providestraining opportunities to more than 23 PhDstudents each year. Our 22 faculty investigators,recruited internationally, include 15 fellowsfrom Ikerbasque, Bizkaia:xede, and Ramón yCajal programs.
CIC bioGUNE research strategy is based onthe firm belief that if talented researchers aregiven the freedom and necessary meansthey will contribute to the solution of thefundamental biological questions. Followingthis policy, scientists at CIC bioGUNE haveestablished research projects in a variety ofareas, including cell growth anddifferentiation, cancer, the innate immuneresponse, liver disease, chromatinremodeling, intracellular trafficking processes,and the structure of proteins, ribosomes andviruses. The projects are summarized in thisannual report. We also firmly believe inthe necessity of creating a lively intellectualenvironment in collaboration with biotechcompanies that fosters creative and
innovative approaches to research andtechnological innovation. Following thisconcept, the Center has set up three jointresearch laboratories with companiesestablished in the Basque Country.
External funding represents a criticalcomponent of CIC bioGUNE’s strategic plan.Since 2006, CIC bioGUNE has received4.1 million € from competitive research grants(mainly from the European Union, NIH, theSpanish Plan Nacional I+D+I, FIS, CIBER andCONSOLIDER programs) and 1 million € fromfoundations (primarily from the BBVAFoundation and Genome Spain) and researchcontracts. Concerted efforts of theadministration of CIC bioGUNE have helpedthe faculty to succeed in the competition forexternal funding. Extramural funding,combined with the generous support of theBasque Government and the RegionalGovernment of Bizkaia, allowed facultyresearch projects to grow and prosper.In fact, in 2008 CIC bioGUNE’s investigatorsauthored 51 scientific publications, in journalswith an average impact factor of 7, andapplied for 3 international patents.
CIC bioGUNE collaborates with the Universityof the Basque Country in the Master ofMolecular Biology and Biomedicineprogramme, reflecting our commitment toinspire and educate a new generation ofscientists. The Center also combines theorganization of research seminars, workshops,and congresses directed to specialists withseries of lectures designed for the generalpublic. CIC bioGUNE, in collaboration withthe other CIC, publishes CIC Network, ajournal dedicated to promote a culture ofresearch and technological innovation in theBasque Country.
CIC bioGUNE research strategy resides inthe firm belief that if talented researchers
are given the freedom and necessarymeans they will contribute to the solution
of the fundamental biological questions.
Prof José M MatoGeneral Director
INTERDISCIPLINARYRESEARCH WILLADVANCE LIFE SCIENCESDISCOVERIES TOWARDPRACTICAL USESFOR SOCIETY
CIC bioGUNE wants to bringtogether under the same roof scientists
from the research centers and thosefrom private companies.
Convinced that the convergence of thelife sciences and the physical sciences,mathematics and engineering can providein the 21st-century an economic growthcomparable to that driven by theconvergence between the physical sciencesand engineering in the 20th-century,the Basque Government recognized lifescience and biotechnology to be an essentialpillar of its economy. To reach this aim, in2002 the Basque Government implementeda plan, known as BioBasque 2010(www.biobasque.org), to drive and
coordinate all efforts in this area.Both the Center for Cooperative Researchin Biosciences in Bizkaia (CIC bioGUNE,www.cicbiogune.es) and the Center forCooperative Research in Biomaterials inGipuzkoa (CIC biomaGUNE,www.cicbiomagune.es) represent thatcommitment. Founded in 2002, CIC bioGUNEestablished its research facilities in the TechnologyPark of Bizkaia (www.parque-tecnologico.net)in January 2005 with the aim to bring togetherunder the same roof scientists from the researchcenters and those from private companies.
The idea was to stimulate interdisciplinaryresearch that will advance life science discoveriestoward practical uses for society. Five yearslater CIC bioGUNE, with around 130 scientistsand technicians, has produced a brandstreamin the Basque Country. As one indicator ofsuccess, the number of companies relatedto bioscience and biotechnology in theBasque Country has increased from 41 in2002 to 72 in 2009 and the sector alreadyaccounts for some 1,500 direct jobs.
At CIC bioGUNE, most of its faculty membershave engaged in their research collaborationswith scientists, engineers and technologyexperts at the universities, other researchand technology centers and biotechcompanies, as well as with medical doctorsin hospitals. One collaborative projectlaunched by CIC bioGUNE, for example, seeksto develop a blood test for the early diagnosisof liver diseases. Another project is trying toidentify genetic variants implicated incommon human complex diseases such astype I diabetes and multiple sclerosis.CIC bioGUNE’s laboratories are also studyingcell-signaling mechanisms involved in cancerinitiation and metastases. These projectscould become a clinical reality within thenext few years.
CIC bioGUNE’s new Structural Biology Unit,which opened in 2007, includes biologists,chemists and engineers working togetherto study the relationships between the
structure of biological molecules and theirintrinsic function. One of the laboratories, forinstance, focuses on the “motors” involvedin universal biological functions whereinteractions between protein and nucleicacids are essential, such as ribosomes duringthe translation process. Another projectlaunched by CIC bioGUNE seeks thecharacterization of proteins and theirinteractions during chromatin remodelingand DNA replication and repair, while yetanother studies the atomic structure of virus.CIC bioGUNE’s laboratories also pursue theanalysis of complex processes such asintracellular trafficking or the structuralcharacterization of enzymes involved in rarediseases such as porfiria, homocystinuria andretinitis pigmentosa. These studies couldprovide new strategies for disease diagnosis,treatment and prevention.
Accelerating these innovations will be themost important challenge of CIC bioGUNEin the coming years. Above all, this will requirefinding more efficient ways to carry outinterdisciplinary work involving the lifesciences researchers, the physicists, physiciansmathematicians and engineers, as well ascollaboration between CIC bioGUNE and thehospitals, technology centers and biotechcompanies.
CarmenGaraizar
President
At CIC bioGUNE members haveengaged in their research
collaborations with scientists,engineers and technology expertsat the universities, other research
and technology centers and biotechcompanies, as well as with medical
doctors in hospitals.
“THE WORLD LOOKS SO DIFFERENT AFTER LEARNING SCIENCE”
Richard Feynman
SCIENTIFICADVISORYBOARD
SCIENTIFICADVISORY BOARD
· Richard H FinnellInstitute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas, USA
· Angela GronenbornDepartment of Structural Biology, University of Pittsburg, USA
· Samir M HanashMolecular Diagnostics, Fred Hutchinson Cancer Research Center, Seattle, USA
· Shelly LuUSC Research Center for Liver Diseases, Keck School of Medicine USC, Los Angeles, California, USA
· Juan RodésLiver Unit, Hospital Clinic, Barcelona, Spain
· Rima RozenDepartment of Pediatrics, Human Genetics and Biology, Mc Gill University-Montreal, Quebec, Canada
· Margarita SalasSevero Ochoa Molecular Biology Center, CSIC, Autónoma University of Madrid, Canto Blanco, Madrid, Spain
· Roger M BurnettProfessor Emeritus, The Wistars Institute, Philadelphia, USA
· Tom BlundellProfessor Emeritus, Department of Biochemistry, University of Cambridge, UK
INDEXRESEARCHUNITS
01 RESEARCHAREAS
TECHNOLOGYPLATFORMS
RESEARCHSUPPORTUNITS
01.1
01.2
02.1
Functional Genomics
Proteomics
Metabolomics
Cell Biology & Stem Cells
Structural Biology
Structural Biology
Genome Analysis
Proteomics & Metabolomics
Gene Silencing
Animal Facilities
Biosafety & Radioactive Protection
Informatics
Maintenance
SERVICEAREAS
ADMINISTRATION &DIRECTOR’S OFFICE
02.2
ADDITIONALINFORMATION
02
03
Funding
Patents
Aids to Recruitment
General Assembly
RESEARCHUNITS
FUNCTIONALGENOMICSUNIT
Genetic analysis is being used to understand the
fundamental mechanisms that underlie hereditary
diseases. This will allow development of therapeutic
strategies and diagnostic systems, both for hereditary
diseases and to predict individual sensitivity to
particular drugs.
The Functional Genomics Unit is concerned with studying the
regulation of the gene expression, in different cell types and during
development. We use sophisticated molecular biology and genetics
techniques to study the genes that control normal biological
processes, like the activation of the innate immune response to
microbial infections and the mechanisms controlling the
development of higher organisms. We are investigating genetic
variants within human populations that are associated with
particular diseases and the possible contribution of nutritional
and environmental influences to the development of pathological
conditions.
FUNCTIONALGENOMICSUNIT
Development of multicellular organisms requires the strict control
of cell division and differentiation. In higher eukaryotes, this control
is exerted by highly conserved signalling pathways, such as the
Transforming Growth Factor-β pathway, and the genes regulated by
them. Among those, the genes encoding the Spalt protein family are
necessary for numerous biological processes and are implicated in
diverse inherited human syndromes, such as the Townes-Brocks or
the Okihiro syndromes, as well as the susceptibility to Ovarian
Carcinoma or Wilms' Tumors. These syndromes include various
malformations, such as dysplastic kidneys (a major cause of renal
failure in infants), supernumerary thumbs, dysplastic ears, sensorineural
hearing loss and severe growth retardation, that might indicate
pituitary dysfunction.
Spalt proteins act as transcriptional repressors and are associated
with chromosomal stability, but the details of their mechanism of
action are still unknown. In our laboratory we try to understand this
mechanism, using the fruit fly Drosophila melanogaster as a model
organism. We are investigating the importance of posttranslational
modifications by sumoylation on the role of Spalt. We have generated
transgenic flies expressing low levels of Sumo using RNA interference
technology. The knockdown flies are unable to move on to adult
stages and stop their growth due to the low levels of ecdysone, the
hormone needed for metamorphosis. We are particularly interested
on the contribution of Spalt to this phenotype, as well as other factors
involved in the synthesis of Ecdysone. The possible role of Spalt
proteins in the regulation of growth is especially intriguing
and constitutes the focus of our research.
Rosa Barrio
Principal Investigator
Collaborations· Dr Rafael Cantera (Stockholm University, Sweden and IIBCE,
Montevideo, Uruguay).
· Dr José Félix de Celis (CBMSO, Madrid, Spain).
· Dr David Martín (Institut de Biologia Molecular de Barcelona,
CSIC, Barcelona, Spain).
· Dr Manuel Salvador Rodríguez (CIC bioGUNE, Bizkaia, Spain).
· Dr James David Sutherland (CIC bioGUNE, Bizkaia, Spain).
Selected Publications1. Talamillo A, Sánchez J, Cantera R, Pérez C, Martín D, Caminero E
and Barrio R. Smt3 is required for Drosophila melanogaster
metamorphosis. Development 135: 1659-1668 (2008).
2. Talamillo A, Sánchez J and Barrio R. Functional analysis of the
SUMOylation pathway in Drosophila. Biochem Soc Trans 36: 868-873
(2008).
3. De Celis JF and Barrio R. Regulation and function of Spalt proteins
during animal development. Int J Dev Biol 52: 2408-2422 (2008).
4. Barrio R, López-Varea A, Casado M and de Celis JF. Characterization
of dSnoN and its relationship to Decapentaplegic signaling in
Drosophila. Dev Biol 306: 66-81 (2007).
Lab Members
Roland HjerpePostdoctoralResearcher
Coralia PérezFernándezTechnician
Ana TalamilloPostdoctoralResearcher
Lab. 1
Leire HerbosoPhD Student
The genetic polymorphisms are variants of the genome that appear
by mutation in some individuals, are transmitted to the descendants
and acquire certain frequency in the population after multiple
generations. It has been estimated that there is a variant for every
1,000 base pairs among the 3,000 million that make the human
genome. The polymorphisms are the base of the evolution and those
that consolidate can be silent or can provide advantages to the
individuals, although they can also contribute to diseases.
With this background in mind, the main objective of this research
group is the identification and validation of genetic variants implicated
in common human complex diseases, in collaboration with national
and international medical researchers.
Most of the projects carried out at the laboratory i) use high-
throughput genotyping or sequencing techniques for simultaneously
examining complete genomes of patients and control individuals to
identify genetic variants; ii) help to develop bioinformatics tools for
the efficient study of the polymorphisms associated with the
susceptibility to a particular disease; and iii) supply biological
interpretation of the obtained results by testing the functionality of
the identified genes, examining their involvement in the aetiology
of diseases and their possible mechanism of action.
The identification of new diagnostic methods for early stages of
certain diseases and of possible targets for the specific drug generation
is of great importance for the development of successful treatment
of many serious human disorders.
Our lab is leading a project for the detailed genetic characterization
of the Basque population in relation to the high incidence of some
inherited diseases in this isolated population. Furthermore, we are
the group responsible of the Genetics Work-Package within the
COEDUCA (Cognition and Education) Consolider–Ingenio 2010
CSD2008-00048 project. In addition, we are participating in several
collaborative projects, namely: i) high density genotyping in the
region 6p21 for the identification of polymorphisms associated with
the susceptibility to Type 1 Diabetes mellitus; ii) identification of new
genes associated with Monogenic Diabetes; iii) high-throughput
genotyping of the MHC (6p21) and LCR (19q3.4) regions in HLA-B27
populations in order to spot genetic variants associated to Ankylosing
Spondylitis; iv) SNP analysis and haplotype structure of cytokine gene
clusters in Multiple Sclerosis patients; v) genetic polymorphisms
association study of Alzheimer Disease by means of high-throughput
SNP genotyping; vi) system biology of Non Alcoholic Fatty Liver
diseases; vii) clinical validation of genetic tests for the evaluation and
therapy selection in colorectal patients (COLOGENETICS); and viii)
EDGeS - Enabling Desktop Grids for e-Science (Grant from the
European Commission's FP7 IST Capacities programme under grant
agreement RI-211727).
Collaborations· Dr Luis Castaño, Dr José Ramón Bilbao and Dr Guiomar Pérez de
Nanclares (Cruces Hospital, Bizkaia, Spain).
· Dr Alfredo Antigüedad and Dr Juan Mari Uterga (Basurto Hospital,
Bizkaia, Spain).
· Dr Carlos López Larrea (Hospital Universitario Central de Asturias,
Asturias, Spain).
· Dr Koen Vandenbroeck and Dr Carlos Matute (Universidad del País
Vasco UPV/EHU, Bizkaia, Spain).
· Dr Manuel Carreiras (Basque Center of Cognition, Brain and Language,
Gipuzkoa, Spain).
· Dr José M Mato & Dr María Luz Martínez-Chantar (CIC bioGUNE,
Bizkaia, Spain).
· Gabriel Carasa (CIC bioGUNE, Bizkaia, Spain).
· Dr Juan Falcón (CIC bioGUNE, Bizkaia, Spain).
· BIOEF foundation (Sondika, Bizkaia, Spain).
· OWL Genomics (Derio, Bizkaia, Spain).
Ana Mª Aransay
Principal Investigator
Lab. 2
Iñaki MendibilTechnician
· Pharmakine (Derio, Bizkaia, Spain).
· AMPTEC (Hamburg, Germany).
· Atos Origin (Madrid, Spain).
Selected Publications1. Hackenberg M, Sturm M, Langenberger D, Falcón-Pérez JM, Aransay
AM. miRanalyzer: a microRNA detection and analysis tool for next-
generation sequencing experiments. Nucl. Acids Res. 37, W68-W76
(2009).
2. Otaegui D, Zuriarrain O, Castillo-Triviño T, Ruíz-Martínez J, Aransay
AM, Olaskoaga J, Marti-Masso JF, López de Munain A. Association
between SYNAPSIN III gene promoter SNPs and multiple sclerosis in
Basque patients. Multiple Sclerosis Journal 15, 1, 124-8 (2009).
3. Martínez-Chantar ML, Vázquez-Chantada M, Ariz U, Martínez N,
Varela M, Luka Z, Capdevila A, Rodríguez J, Aransay AM, Matthiesen
R, Yang H, Calvisi DF, Esteller M, Fraga M, Lu SC, Wagner C, Mato JM.
Loss of the Glycine N-Methyltransferase Gene Leads to Steatosis and
Hepatocellular Carcinoma in Mice. Hepatology 47, 4, 1191-9 (2008).
4. Castellanos-Rubio A, Martín-Pagola A, Santín I, Hualde I, Aransay
AM, Castaño L, Vitoria JC, Bilbao JR. Combined functional and positional
genetic information for the identification of susceptibility genes in
celiac disease. J. Gastroenterology 134, 3, 738-746 (2008).
5. Santín I, Castellanos-Rubio A, Aransay AM, Castaño L, Vitoria JC,
Bilbao JR. The functional R620W variant of the PTPN22 gene is
associated with celiac disease. Tissue Antigens 71, 3, 247-9 (2008).
Lab MembersLiher ImazPhD Student
Karin SchlangenPostdoctoralResearcher
Models of the innate immune response and genetic diseases in the
fly Drosophila.
The fruit-fly, Drosophila melanogaster, represents a very powerful
model to study biological processes due to its ease of culture, rapid
generation time and the sophisticated genetic tools that have been
developed for this organism.
As an example, the Toll receptor in humans, which is involved in the
recognition of pathogens, was identified by homology to the
Drosophila Toll gene.
In humans, the immune response consists of an immediate “innate”
response (mediated via antimicrobial peptides) and a delayed
“acquired” response (mediated via antibodies). In response to microbial
challenge, insects sythesize antibiotic peptides, activate macrophage-
like cells and mount a melanization response, but the antibody
mediated response is absent.
The major objective of our laboratory is to understand the mechanisms
of activation and degradation of the Necrotic protein in Drosophila.
In 1999, we identified Necrotic as a member of the serpin (serine
protease inhibitor) family, closely resembling human protease
inhibitors involved in the inflammatory response. More specifically,
Necrotic controls initiation of the extracellular proteolytic cascade
which activates the immune response to microbial infections. Serpin
turnover in biological systems tends to be extremely rapid and serpin-
degradation mechanisms may share genetic components with
mechanisms of misfolded-peptide clearance that underlie
diseases such as Alzheimer's and Parkinson's. These diseases have in
Lab. 3common the over-accumulation of peptides which prevent the
normal functioning of nerves.
An additional interest of our laboratory is the cryopreservation of
Drosophila stocks. The maintenance of genetic strains has reached
a crisis point in the Drosophila community, due to the lack of a
practical method for long-term storage of the many thousands of
unique fly strains. For this reason we are trying to develop a method
of long-term cryopreservation of stocks.
Collaborations· Dr Jean-Marc Reichhart (ICBM, Strasbourg, France).
· Dr David Lomas (Department of Medicine, University of Cambridge, UK).
· Dr John Morris (Asymptote Ltd, Cambridge, UK).
Selected Publications1. Garrett M, Fullaondo A, Troxler L, Micklem G, Gubb D. Identification
and analysis of serpin-family genes by homology and synteny across
the 12 sequenced Drosophilid genomes. MBC Genomics, 10: 489
(2009).
2. Soukup S, Culi J, Gubb D. Uptake of the Necrotic Serpin in Drosophila
Melanogaster via the Lipophorin Receptor-1. PLoS Genet
5(6):e1000532 (2009).
3. Lin Y, Gubb D. Molecular dissection of Drosophila Prickle isoforms
distinguishes their essential and overlapping roles in planar cell
polarity. Dev Biol 325: 386-399 (2009).
4. Yan J, Huen D, Morely T, Johnson G, Gubb D, Roote J, Adler P. The
multiple-wing-hairs gene encodes a novel GBD-FH3 domain-
containing protein that functions both prior to and after wing hair
initiation. Genetics 180 219-28 (2008).
5. Pelte N, Robertson A, Zhou Z, Belorgey D, Dafforn T, Jiang H, Lomas
D, Reichhart J-M, Gubb D. Immune Challenge induces N-terminal
cleavage of the Drosophila serpin Necrotic. Insect Biochemistry Mol
Biol. l 36: 37-46 (2006).
David GubbPrincipal Investigator
Lab MembersVeronikaMikitovaPostdoctoralResearcher
Laura BárcenaTechnician
Arantza SanzParraTechnician
Ubiquitination of neuronal proteins is an essential regulatory
mechanism of brain function, and its failure is associated to a number
of neurodegenerative conditions, including Parkinson’s and Alzheimer’s
diseases. Over the last two decades, much has been learnt from
studies on yeast and mammalian cell culture regarding the regulation
of ubiquitination at the molecular level. However, our understanding
of ubiquitination pathways within the context of whole organisms
is still very poor.
Genetic studies using Drosophila as a model system have identified
a number of ubiquitination pathways essential for neuronal function,
but the evidence for actual ubiquitination of the candidate substrates
has at best been indirect. Whereas the anatomic complexity of
Drosophila is far simpler than ours, most molecular mechanisms
governing neuronal cell function are actually highly conserved.
However, due to its relative complexity and tissue heterogeneity,
even Drosophila labs have often used cell culture for validating
candidate substrates of ubiquitin, on the assumption that if a protein
can be ubiquitinated in a given cell line, it might be ubiquitinated as
well in any other cell type. However, ubiquitination is used to regulate
cell function in a context-specific manner, and its roles are very likely
to be regulated differently in different tissues. For example, it is well
known that E3 ligase expression patterns differ enormously. Since
most characterised genomes code for hundreds of E3 ligases, it is
expected that ubiquitination pathways will be tissue specific.
We are developing a novel strategy for the efficient isolation of
neuronal ubiquitin conjugates from flies. The approach is based on
the in vivo biotinylation of ubiquitin expressed in a tissue-specific
manner. Taking advantage of the strength of the streptavidin-biotin
Lab. 4interaction, we are capable of enriching the ubiquitinated proteins
from Drosophila neurons up to levels not achieved by any other
approach until now. This technique is allowing us to isolate and
identify all neuronal proteins that are ubiquitinated, to resolve whether
they are mono or polyubiquitinated, and even to quantify for each
ubiquitin substrate which percentage was ubiquitinated in the
neuronal tissue of the living fly. We are also identifying the position
at which those proteins are being ubiquitin-modified.
Our lab has a number of ongoing projects to take advantage of the
technology we have developed. We are comparing the ubiquitination
profile of the developing brain with that of the adult brain, as well
as with the ubiquitination profile of other tissues. We are looking at
the specific substrates of a few important E3 ligases, like Highwire,
Ariadne1 and dUbE3A, this last one being the E3 ligase whose loss
of function causes Angelman syndrome, a genetic neurological
disorder. We are also looking at the ubiquitination profile in fly models
of polyglutamine diseases, to try to discern whether the ubiquitination
associated with those neurodegenerative disorders is the cause or
the effect of the disease. Additionally, we are looking at SUMOylation
using a very similar approach.
Collaborations· Dr Junmin Peng (Emory University School of Medicine, Atlanta, GA, USA).
· Dr Andrea Brand (Wellcome Trust Cancer Research UK Gurdon
Institute, Cambridge, UK).
· Dr Catherine Lindon (Dept of Genetics, University of Cambridge,
Cambridge, UK).
· Dr Rosa Barrio (CIC bioGUNE, Bizkaia, Spain).
· Dr Alberto Ferrus (Instituto Cajal CSIC, Madrid, Spain).
· Dr Janice Fischer (University of Texas, Austin, TX, USA).
Selected Publications1. Religa TL, Markson JS, Mayor U, Freund SMV, Fersht AR. Solution
structure of a protein denatured state and folding intermediate.
Nature 437:1053-6 (2005).
Ugo MayorPrincipal InvestigatorIkerbasque Research Professor
So Young LeeTechnician
Lab MembersJuan ManuelRamírez SánchezPhD Student
Maribel FrancoPostdoctoralResearcher
2. Mayor U, Guydosh NR, Johnson CM, Grossmann JG, Sato S, Jas GS,
Freund SMV, Alonso DOV, Daggett V and Fersht AR. The complete
folding pathway of a protein from nanoseconds to microseconds.
Nature 421:863-7 (2003).
3. Mayor U, Grossmann JG, Foster NW, Freund SMV and Fersht AR.
The denatured state of Engrailed homeodomain under denaturing
and native conditions. Journal of Molecular Biology 333:977-91 (2003).
4. Mayor U, Johnson CM, Daggett V and Fersht AR. Protein folding
and unfolding in microseconds to nanoseconds by experiment and
simulation. Proc. of the National Academy of Sciences of the USA
97:13518-22 (2000).
PROTEOMICSUNIT
The map of human proteins will make it possible to
find new diagnostic markers for different pathologies.
The availability of the complete sequence of certain genomes,
especially the human genome, offers new opportunities for
biological research.
The goal of the Proteomics Unit is to identify proteins involved in
some physiological processes and also to characterize the
interactions between them.
Such functional characterization may allow comparisons between
the protein pattern present in diseased tissue versus healthy tissue
and consequently, it may be possible to establish the specific
"proteomic fingerprint" of a pathological state. Detailed protein
studies may reveal potential molecular markers associated with
disease progression and lead to possible therapeutic targets.
PROTEOMICSUNIT
Lab. 1
Transmissible spongiform encephalopathies (TSEs) are fatal
neurodegenerative disorders affecting both humans and animals.
TSEs can be of genetic, sporadic or infectious origin. The infectious
agent associated with TSEs, termed prion, appears to consist of a
single protein, an abnormal conformer (PrPSc) of a natural host protein
(PrPC), which propagates by converting host PrPC into a replica of
itself. One of the characteristics of prions is their ability to infect some
species and not others. This phenomenon is known as transmission
barrier. Interestingly, prions occur in the form of different strains that
show distinct biological and physicochemical properties, even though
they are encoded by PrP with the same amino acid sequence, albeit
in presumably different conformations. In general, the transmission
barrier is expressed by an incomplete attack rate and long incubation
times (time from the animal inoculation until the onset of the clinical
signs) which become shorter after serial inoculation passages.
Compelling evidence indicates that the transmission barriers are
closely related to differences in PrP amino acid sequences between
the donor and recipients of infection, as well as the prion strain
conformation. Unfortunately, the molecular basis of the transmission
barrier phenomenon and its relationship to prion strain conformations
is currently unknown and we cannot predict the degree of a species
barrier simply by comparing the prion proteins from two species. We
have conducted a series of experiments using the Protein Misfolding
Cyclic Amplification (PMCA) technique that mimics in vitro some of
the fundamental steps involved in prion replication in vivo, albeit with
accelerated kinetics. The in vitro generated prions possess key prion
features, i.e., they are infectious in vivo and maintain their strain
specificity. We have used PMCA to efficiently replicate a variety of
prion strains from, among others, mice, hamsters, bank voles, deer,
cattle, sheep, and humans. The correlation between in vivo data and
our in vitro results suggest that PMCA is a valuable tool for assessing
the strength of the transmission barriers between diverse species
and for different prion strains; we are using the method to determine
which amino acids in the PrPC sequence contribute to the strength
of the transmission barrier. These studies are proving very useful in
evaluating the potential risks to humans and animals, of not only
established prion strains, but also new (atypical) strains. For example,
while classical sheep scrapie is unable to cross the human transmission
barrier in vitro, bovine spongiform encephalopathy (BSE) propagated
in sheep does so efficiently. In addition, we have also generated
prions that are infectious to species hitherto considered to be resistant
to prion disease.
Collaborations· Dr Glenn Telling (Department of Microbiology, Immunology and
Molecular Genetics, University of Kentucky, Lexington, KY, USA).
· Dr Charles Weissmann (Department of Infectology, Scripps Research
Institute, Jupiter, FL, USA).
· Dr Adriano Aguzzi (Institute of Neuropathology, University Hospital
Zurich, Zurich, Switzerland).
· Dr Juan María Torres (Centro de Investigación en Sanidad Animal,
INIA, Madrid, Spain).
· Dr Enric Vidal and Dr Martí Pumarola (Departament de Medicina i
Cirugia Animals, Universitat Autònoma de Barcelona, Barcelona,
Spain).
Selected Publications1. Castilla J, Morales R, Saá P and Soto C. Propagation of prion strains
in vitro. EMBO J. 27, 2557-2566 (2008).
2. Castilla J, Gonzaléz D, Saá P, Morales R, de Castro J and Soto C.
Crossing species barrier by in vitro replication of protein misfolding
generates new infectious prions. Cell. 134, 757-768 (2008).
3. Green KM, Castilla J, Seward TS, Napier DL, Jewell JE, Soto C and
Telling GC. Accelerated High Fidelity Prion Amplification Within and
Across Prion Species Barriers. PLOS Pathogens. 4, 1-12 (2008).
Joaquín Castilla
Principal InvestigatorIkerbasque Research Professor
Alberto MarinaTechnician
4. Saá P, Castilla J and Soto C. Pre-symptomatic detection of prions in
blood. Science. 313, 92-4 (2006).
5. Soto C, Estrada L and Castilla J. Amyloids, prions and the inherent
infectious nature of misfolded protein aggregates. Trends in
Biochemical Sciences. 31, 150-155 (2006).
Lab Members
NataliaFernández-BorgesPostdoctoralResearcher
Nagore SacristánTechnician
Iker UriartePostdoctoralResearcher
Emma LovisaHelena JakobssonPostdoctoralResearcher
Adhesion between cells, as well as adhesion of cells to substrates, is
a fundamental property of multicellular organisms. Changes in cell
adhesion can give rise to defects in development and loss of tissue
integrity that contributes to human disease. During cancer metastasis,
transformed cells of a solid tumor can disperse and become more
motile, traveling to remote sites where they may form secondary
tumors. Cells must leave the primary tumor, enter and exit the
circulatory system by crossing endothelial layers, and populate the
secondary site - all steps that require remodelling and changes
in cell adhesion structures.
Our work focuses on PET-LIM proteins, a small family of scaffolding
proteins that may regulate the formation of protein complexes
involved in diverse cellular processes, including cell spreading,
adhesion and polarity. The testin protein (TES) exhibits dynamic
localisation within cells and shuttles between the nucleus and the
integrin-based focal adhesions formed between cells and substrates.
Loss of TES is observed in several tumor types and mice lacking TES
exhibit aggressive tumor growth, pointing to its role as a tumor
suppressor. We are using screening by RNAi to uncover additional
factors in the TES tumor suppression pathway. Also, to understand
how TES is regulated, we are using biochemistry, mutational analysis
and structure-based approaches to uncover intramolecular interactions
that control the ability to form complexes with known and novel TES
ligands. Lastly, several PET-LIM family members are farnesylated and
may regulate multiprotein complex assembly at the plasma membrane
or close to organelles. One of these, Prickle3, dynamically localises to
cell-cell adhesions. Further examination of this class of PET-LIMs will
reveal if they are also cancer-related or have novel roles in development
and disease.
Collaborations· Dr Puri Fortes, Dr Rubén Hernández (Centro de Investigación Médica
Aplicada, Universidad de Navarra, Pamplona, Spain).
· Dr Roberto Martínez, Dr Ricardo Rezola, Dr María Jesús Michelena
(Instituto Oncológico, San Sebastián, Gipuzkoa, Spain).
· Dr Rosa Barrio (CIC bioGUNE, Bizkaia, Spain).
Selected Publications1. Garvalov BK, Higgins TE, Sutherland JD, Zettl M, Scaplehorn N,
Köcher T, Piddini E, Griffiths G, Way M. The conformational state of
Tes regulates its zyxin-dependent recruitment to focal adhesions.
J Cell Biol. 161(1):33-39 (2003).
Lab MembersItziar Martín RuízTechnician
Lab. 2James D Sutherland
Principal Investigator
The covalent conjugation of ubiquitin and ubiquitin-like molecules
to different substrates has become one of the most widely investigated
post-translational modifications. Modified substrates include proteins
controlling an extensive array of essential processes, such as protein
degradation via the 26S proteasome, regulation of transcription, the
cell cycle and oncogenesis.
The ubiquitin family of molecules can be attached to protein substrates
as monomers and polymers. Although a considerable amount of
data on many aspects of ubiquitin and ubiquitin-like mediated
processes is available, many aspects regarding the modification-
specific and chain-type recognition of conjugated substrates, as well
as the molecular processes engaged after protein conjugation with
the various ubiquitin-like modifiers such as SUMO-1, SUMO-2, SUMO-
3 and NEDD8, remain obscure. To address these questions our main
models are: 1) Iκβα a and A20 proteins -both proteins are natural
inhibitors of the NF-κβ transcription factor, which conditions its
transcriptional activity during the immune and inflammatory responses
and 2) the tumour suppressor p53.
Our specific objectives are:
a. Identification of specificity motifs in the target proteins determining
the preferential recognition by modifier-protein ligases (E3s), and the
use of these motifs to isolate, identify and study the role of interacting
proteins participating in the response generated by such modifications.
b. Applying this knowledge to develop high troughput screenings
methods (HTS) to isolate new drugs that can be used to treat
pathologies where our protein models are implicated.
Manuel Rodríguez MedinaPrincipal Investigator
Lab. 3c. Developing new strategy and applications to isolate and identify
ubiquitylated proteins in vivo from cell cultures as well as for tissues
and organs from animal models where the Ubiquitin-Proteasome
Pathway appears to be at the origin of drug resistance or pathologies
such as cancer or neurodegenerative disorders.
The knowledge obtained using these approaches will most certainly
contribute significantly to generating new concepts of the role of
members of the ubiquitin family in the regulation of molecular events,
in an important number of essential cellular processes in health and
disease.
Collaborations· Dr Patrick England (Pasteur Institute, Paris, France).
· Dr Ron Hay (Dundee University, Scotland, UK).
· Dr Rosa Farrás (Centro de Investigación Principe Felipe,
Valencia, Spain).
· Dr Carmen Rivas (CNB, CSIC, Madrid, Spain).
· Dr Rosa Barrio (Functional Genomics Unit, CIC bioGUNE, Bizkaia, Spain).
· Dr Edurne Berra (Cell Biology Unit, CIC bioGUNE, Bizkaia, Spain).
· Dr José M Mato (Metabolomics Unit, CIC bioGUNE, Bizkaia, Spain).
· Dr María Luz Martínez-Chantar (Metabolomics Unit, CIC bioGUNE,
Bizkaia, Spain).
Selected Publications1. Hjerpe R, Aillet F, Torres-Ramos M, Lang V, Farrás R, Hay RT and
Rodríguez MS. Mdm2 mediates multiple mono-ubiquitin-dependent
proteasomal degradation of p53. Submitted (2009).
2. Hjerpe R, Aillet F, Lopitz-Otsoa F, Lang V, England P and Rodríguez
MS. Using Tandem Ubiquitin Binding Entities (TUBEs) to isolate
polyubiquitylated proteins. EMBO rep Octubre 2009.
3. Hjerpe R and Rodríguez MS. Alternative UPS drug targets upstream
the 26S proteasome. International Journal of Biochemistry and Cell
Biology. 40, 1126-1140 (2008).
Fabienne AilletPostdoctoralResearcherCIBERehd Fellow Member
Fernando LopitzPostdoctoralResearcher
Valerie LangPostdoctoralResearcher
4. Rubio A, Guruceaga E, Vázquez-Chantada M, Sandoval J, Martínez-
Cruz LA, Segura V, Sevilla JL, Podhorski A, Corrales FJ, Torres L, Rodríguez
MS, Aillet F, Ariz U, Martínez Arrieta F, Caballería J, Martín-Duce A, Lu
SC, Martínez-Chantar ML, Mato JM. Identification of a Gene-pathway
associated with non-alcoholic esteatohepatitis. J. Hepatology 46,
708-718 (2007).
Lab Members
METABOLOMICSUNIT
Metabolomics provides knowledge to identify the
metabolites present in a biological sample, and is
the simplest, cheapest and most efficient method
to diagnose diseases.
Metabolomics focuses on the study of metabolites. These small
molecules are the last step in the biological process initiated with
gene expression. The study of human metabolome is a very efficient
method to identify possible markers and determine if an individual
person is going to suffer from a disease, helping to diagnose a
specific pathology.
In mammals, specially in human, the liver plays an important role
in metabolomic equilibrium. In a pathological situation like diabetes
mellitus, obesity, steatohepatitis or cirrhosis, a failure in the
regulation of the mechanism maintaining the metabolomic
equilibrium takes place. The aim of this unit is to identify the
essential metabolites involved in signaling pathway regulation
and analyze the mechanism of the progression and development
of liver diseases. This knowledge will help us to understand the
mechanism and the relationship existing between essential
metabolites and proliferation, cellular death and cellular
metabolism.
METABOLOMICSUNIT
Non-alcoholic fatty liver disease (NAFLD) is currently the most frequent
chronic liver disease in western countries affecting about 20-30% of
adults above age 20. NAFLD is characterized by the accumulation of
fat in the liver (steatosis). Although generally asymptomatic, 10-40%
of NAFLD patients, depending on the population selected, develop
non-alcoholic steatohepatitis (NASH), which is characterized by the
presence of steatosis with inflammation, necrosis and fibrosis. NASH
is a progressive disease of the liver that may progress to cirrhosis and
hepatocellular carcinoma (HCC). Obesity is a major risk factor for the
development of NAFLD. However, the observation that about half
the patients with NAFLD are not obese indicates that there are factors
(nutritional, genetic and environmental), independent of the ingestion
and lipid metabolism that strongly affect the accumulation of fat in
the liver.
In my laboratory we have used gene-knockout technology to study
how mouse genes regulate liver metabolism and fat accumulation
–a research that provides relevant information on the hepatic
metabolism in humans and how hepatic fat accumulates when there
is a metabolic imbalance–. Using this technology, we have identified
that S-adenosylmethionine (SAMe, a metabolite of methionine) plays
a crucial role as a regulator of liver metabolism and hepatocyte
proliferation and how both, a chronically low levels and excess of
hepatic SAMe leads to NASH and HCC. The mechanism by which
SAMe regulates liver function involves histone- and DNA-methylation
as well as regulation of AMP-activated protein kinase (AMPK), the
main enzyme involved in the regulation of hepatic metabolism.
Other research lines in my laboratory include: the identification of
non-invasive serum biomarkers that differentiate between steatosis
José M Mato
Principal Investigator
Lab. 1and NASH using high-throughput metabolic technology – at present
the gold standard for the diagnosis of NAFLD is histological
examination of a liver biopsy specimen, which is an expensive, invasive
and subjective procedure associated with potential complications
and prone to sampling error – the identification of gene variants
associated with the development of NASH; and the characterization
and comprehensive proteome profiling of exosomes secreted by
hepatocytes. Exosomes are 40-100 nm membrane vesicles of endocytic
origin secreted by most cell types that mediate communication
between cells, facilitating processes such as antigen presentation
and in trans-signaling to neighboring cells.
Collaborations
· Dr Shelly C Lu (University of Southern California, Los Angeles,
CA, USA).
· Dr Conrad Wagner (Vanderbilt University School of Medicine,
Nashville, TN, USA).
· Dr Richard H Finnell (Texas Institute for Genomic Medicine,
Houston, TX, USA).
· Dr Juan Caballería (Hospital Clínic de Barcelona, Barcelona, Spain).
· Dr CB Rountree (Penn State Children's Hospital, Hershey, PA, USA).
· Dr Jian-Min Yuan (University of Minnesota, Minneapolis, MN, USA).
· Dr Luis Torres (Universidad de Valencia, Valencia, Spain).
· Dr Yannick Le Marchand-Brustel (Universitaire Archimed, INSERM,
Nice, France).
· Dr Jonathan Barr (OWL Genomics, Derio, Bizkaia, Spain).
· Dr Carlos Simón (Fundación IVI, Valencia, Spain).
Selected Publications1. Varela-Rey M, Fernández-Ramos D, Martínez-López N, Embade N,
Gómez-Santos L, Vázquez-Chantada M, Rodríguez J, Luka Z, Wagner
C, Lu SC, Martínez-Chantar ML, Mato JM. Impired liver regeneration
in mice lacking glycine N-methyltransferase. Hepatology.
Aug;50(2):443-52 (2009).
2. Vázquez-Chantada M, Ariz U, Varela-Rey M, Embade N, Martínez-
López N, Fernández-Ramos D, Gómez-Santos L, Lamas S, Lu SC,
Martínez-Chantar ML, Mato JM. Evidence for LKB1/AMP-activated
protein kinase/ endothelial nitric oxide synthase cascade regulated
by hepatocyte growth factor, S-adenosylmethionine, and nitric oxide
in hepatocyte proliferation. Hepatology. Feb;49(2):608-17 (2009).
3. Ding W, Mouzaki M, You H, Laird J, Mato JM, Lu SC, Rountree CB.
CD 133 + Liver Cancer Stem Cells from Methionine Adenosyl
Transferase 1A Deficient Mice Demonstrate Resistance to TGF-β
induced apoptosis. Hepatology; 49:1277-86 (2009).
4. Mato JM, Martínez-Chantar ML, Lu SC. Methionine Metabolism and
Liver Disease. Annu Rev Nutr. Aug 21;28:273-293 (2008).
Lab Members
Lab Members attachedto external projects
Richard H FinnellVisitingScientific
David FernándezRamosPhD Student
Juan Luis GarcíaRodríguezPhD Student
Mercedes VázquezChantadaPostdoctoralResearcher
Javier CondePhD Student
Juan ManuelFalcónPostdoctoralResearcher
EsperanzaGonzález JiménezTechnician
Nieves EmbadePostdoctoralResearcher
Marcella SiniVisitingResearcher
Miriam PérezCormenzanaPlatformSpecialist
Non-alcoholic fatty liver disease (NAFLD) is a clinical-pathological
term that includes a spectrum of alterations ranging from the simple
accumulation of triglycerides in the hepatocytes (steatosis) to steatosis
with hepatic inflammation (steatohepatitis or NASH). NASH, in turn,
also progresses to cirrhosis and HCC. The mechanisms that lead to
the manifestation of NASH are not clear, but it is a condition associated
with obesity, insulin resistance, and diabetes.
Since the incidence of these diseases is increasing, the prevalence of
NASH is also expected to increase in coming years (today it varies
between 13 to 15 % of the population). NASH is now considered as
an emerging disease in USA and occidental countries. Nowadays,
lacking accurate, sensitive diagnostic test, distinguishing steatosis
from steatohepatitis requires the use of invasive techniques like liver
biopsy. In summary, the lack of information about the factors
implicated in the NASH pathogenesis, as well as in the prognostics
characteristics and the treatment of this pathology, emphasize the
need of new approaches aimed at understanding the mechanisms
implicated in the development of NASH and HCC. In response to
these needs we propose a multidisciplinary research project to study
these pathologies.
Over the last few years, we have elucidated some of the molecular
mechanisms of SAMe regulated proliferation, regeneration and
apoptosis and identified downstream targets contributing to the
abnormal hepatic lipid metabolism and proliferation in both
MAT1A-KO and GNMT-KO mice, both with chronically abnormal levels
of SAMe. The most important projects proposed are the following
ones: 1) Examine SAMe’s regulation of HGF-mediated hepatocyte
proliferation. Hepatocyte growth factor (HGF) activates AMP-activated
Mª Luz Martínez Chantar
Principal Investigator
Lab. 2protein kinase (AMPK), which is required for hepatocyte proliferation.
Our new data also show cross-talks between AMPK and nitric oxide
synthase in modulating the proliferative effect of HGF. How SAMe
regulates these pathways will be elucidated. 2) We have isolated a
cancerous cell line (SAMe-D) from MAT1A-KO HCC. Our aim is to
characterize this cell line to learn more about how cancer develops
in MAT1A-KO mice liver. This is highly relevant in cases with liver
cirrhosis where MAT1A expression is often low or absent and the risk
of HCC is high. 3) Identify mechanisms of malignant degeneration
when SAMe metabolism is altered. Both chronic SAMe deficiency
and excess result in fatty liver and HCC. Successful completion of the
proposed tasks should greatly enhance our understanding of SAMe’s
role in liver health and pathology and help identify patients that will
benefit from its therapeutic use.
Collaborations· Dr Shelly C Lu (University of California, Los Angeles, CA, USA).
· Dr Myriam Gorospe (NIH, Baltimore, MD, USA).
· Dr Anna Maeh Diehl (Duke University Medical Center, Durham,
NC, USA).
· Dr Richard Finnell (Department of Nutrition and Food Science,
Houston, TX, USA).
Selected Publications1. Tomasi ML, Iglesias-Ara A, Yang H, Ramani K, Feo F, Pascale MR, Martínez-
Chantar ML, Mato JM, Lu SC. S-Adenosylmethionine Regulates
Apurinic/Apyrimidinic Endonuclease 1 Stability: Implication
Hepatocarcinogenesis. Gastroenterology. 136:1025-1036 (2009).
2. Vázquez-Chantada M , Ariz U, Varela-Rey M, Martínez-López Nuria,
Embade N, Fernández-Ramos D, Gómez-Santos, Lu SC, Martínez-Chantar
ML, Mato JM. Evidence for an LKB1/AMPK/eNOS Cascade
Regulated by HGF, S-Adenosylmethionine and NO. Hepatology 49:
608-617 (2009).
3. Varela-Rey M, Embade N, Ariz U, Lu SC, Mato JM, Martínez-Chantar
ML. Non-alcoholic steatohepatitis and animal models: Understanding
the human disease. Int J Biochem Cell Biol. 41:969-976 (2009).
4. Martínez-Chantar ML, Vázquez-Chantada M, Ariz U, Martínez N, Varela
M, Luka Z, Capdevila A, Rodríguez J, Aransay AM, Matthiesen R, Yang H,
Calvisi DF, Esteller M, Fraga M, Lu SC, Wagner C, Mato JM. Loss of the
glycine N-methyltransferase gene leads to steatosis and hepatocellular
carcinoma in mice. Hepatology 47:1191-1199 (2008).
Lab Members
Naiara BerazaPostdoctoralResearcher
BegoñaRodríguezIruretagoyenaTechnician
Itziar FradesPhD Student
Nuria MartínezLópezPhD Student
Marta VarelaPostdoctoralResearcherCIBERehd Fellow Member
Ashwin WoodhooPostdoctoralResearcher
CELL BIOLOGY& STEM CELLSUNIT
We investigate the molecular changes that occur in
cells and their genomes in response to different
stimuli.
We work on projects of basic and applied research that investigate
important cellular processes such as cell proliferation,
differentiation, maintenance of pluripotency and adaptation to
low oxygen availability. Scientific interests of the laboratories in
the Unit include the signalling pathways activated by steroid
hormones, Wnt family growth factors and hypoxia, the genetic
changes occurring during carcinogenesis and the functional and
spatial organisation of the genome. Our aims are to understand
the relationship between these processes and pathologies such
as cancer, neurodegenerative disease and ischemia and to generate
new diagnostic and therapeutic tools.
CELL BIOLOGY &STEM CELLS UNIT
Bruno SimõesPhD Student
ValentineComaillsPhD Student
Oihana IriondoPhD Student
Marco PivaPhD Student
The main objective of the laboratory is to gain further insight into
the roles that steroid hormone receptors play in normal breast tissue
and during breast cancer development. Furthermore, the influences
of estrogen, other signalling factors and the microenvironment in
breast stem cells and in their transformation into cancer initiating
cells are being explored.
Following the interest of the laboratory in the initiation and progression
of breast cancer, three stem/progenitor cell populations were identified
in the human mammary gland. These populations are currently being
characterised in more detail and their responses to hormones and
other signals are being investigated. In addition, both normal breast
and breast tumour cells are being propagated as mammospheres to
facilitate comparative studies of stem/progenitor cell self-renewal
and differentiation in response to various treatments.
The cancer stem cell hypothesis implies that stem/progenitor cells
are more resistant to current therapies used to treat patients. Tamoxifen
is one of the most commonly used endocrine treatments for estrogen-
responsive breast cancer, although development of resistance is a
frequent clinical problem. Breast cancer stem/progenitor cells that
are resistant to tamoxifen have been generated and the responses
of these cells to chemotherapy drugs and other factors are currently
being studied.
The various approaches undertaken in the laboratory should
contribute to a better knowledge of the molecular profile of breast
stem cells and the responses of both normal and cancer breast
stem/progenitor cells to their cellular environment.
Lab. 1Collaborations· Dr José Antonio López Ruiz (PreteImagen, Bilbao, Bizkaia, Spain).
· Dr Shyamala Maheswaran (MGH, Harvard Medical School,
Boston, MA, USA).
· Dr José Luis Toca-Herrera (CIC biomaGUNE, Gipuzkoa, Spain).
Selected Publications1. Moreno-Flores S, Benitez R, Vivanco MdM, Toca-Herrera JL. Stress
relaxation microscopy: Imaging local stress in cells. J Biomech. [Epub
ahead of print] (2009).
2. Vivanco MdM. Biomarkers in breast cancer. Chapter 7 in:
Bioinformatics Methods in Clinical Research (2009). Eds. J Walker and
R Matthiesen, Humana Press (2009).
3. Krützfeldt M, Ellis M, Weekes DB, Bull JJ, Eilers M, Vivanco MdM,
Sellers WR, Mittnacht S. Selective ablation of retinoblastoma protein
function by the RET finger protein. Molecular Cell 18, 213-224 (2005).
4. Clayton H, Titley I and Vivanco MdM. Growth and differentiation
of progenitor/stem cells derived from the human mammary gland.
Exp Cell Res 297, 444-460 (2004).
Lab Members
María del Mar Vivanco
Principal Investigator
Gemma ReverterPostdoctoralResearcher
Mª ÁngelesRábanoTechnician
The Wnt signalling pathway plays an important role in cell growth
and differentiation and is frequently activated in cancer. Our goals
are to understand how Wnts, their antagonists and their effectors
control cell growth and differentiation and to use the technological
platforms at CIC bioGUNE to characterise the cellular responses to
Wnt ligands. We study these aspects in two contexts – prostate cancer
(PCa) progression and neuronal differentiation.
We examined Wnt gene expression in PCa and found that Wnt-11 is
upregulated in hormone-refractory PCa. Gene silencing and
overexpression were used to show that Wnt-11 alters the survival
and neuroendocrine-like differentiation of PCa cells. Wnt gene
expression was also analysed during retinoic acid induction of neural
differentiation of human embryonal carcinoma (hEC) cells. Three Wnts
were identified that might play roles in this process, one of which is
Wnt-11. Ongoing studies involve characterisation of the Wnt signals
that control survival and differentiation of PCa and hEC cells. The sFRP
and Dickkopf families of secreted Wnt antagonists have also been
characterized and Dkk3 and sFRP1 were found to be downregulated
in PCa. We are presently studying the function of Dkk3 in cell
differentiation in more detail.
Finally, we are characterising the Wnt effectors Axin and glycogen
synthase kinase-3 (GSK-3), which together act to inhibit Wnt/beta-
catenin signalling. Phosphorylation sites in Axin have been identified
that play a role in the regulation of GSK-3 activity. We are now analysing
the functions of the different isoforms of GSK-3 in PCa and in neuronal
differentiation.
Lab. 2
Zafira CastañoPostdoctoralResearcher
Mercedes CaroTechnician
Víctor ManuelCampaPostdoctoralResearcher
Collaborations· Dr Akira Kikuchi (Hiroshima University, Hiroshima, Japan).
· Dr Jonathan Waxman (Imperial College London, London, UK).
· Dr Phillip Gordon-Weeks (MRC Centre for Developmental
Neurobiology, Kings College London, London, UK).
· Dr María del Mar Vivanco (CIC bioGUNE, Bizkaia, Spain).
Selected Publications1. Kawano Y, Diez S, Uysal-Onganer P, Darrington RS, Waxman J,
Kypta R. sFRP1 is a negative regulator of androgen receptor activity
in prostate cancer. British Journal of Cancer, 100, 1165-1174 (2009).
2. Kypta R. Wnt signalling in The Encyclopedia of Cancer, 2nd Edition
Edited by Manfred Schwab, Springer Press (2009).
3. Castano Z, and Kypta R. Housekeeping Proteins: Limitations as
References During Neuronal Differentiation. The Open Neuroscience
Journal, 2, 36-40 (2008).
4. Kypta R. GSK-3 inhibitors and their potential in the treatment of
Alzheimer's disease. Expert Opinion in Therapeutic Patents 15, 1315-
1332 (2005).
Lab Members
Robert Kypta
Principal Investigator
Rocío JiménezAlonsoPhD Student
The laboratory of Cytogenomics is focused on studying genome
organization at the cellular level, in particular during liver
carcinogenesis. Our research project “Cytogenomics of benign and
malignant lesions of the liver”, aims to characterize the profile of
genome alterations of liver tumours arising in human and in different
mouse models of the disease. To this end, conventional and molecular
cytogenetic methods, such as FISH, SKY and array-CGH are currently
used in the laboratory.
The group is also interested in investigating the 3-dimensional
arrangements of chromosomes and genes in the interphase nucleus
during carcinogenesis. The project “Organization of the genome in
the interphase nucleus” intends to generate a 3D map of those
chromosomes and genes recurrently involved in abnormalities in
hepatomas using interphase FISH with whole-chromosome painting
and locus-specific probes combined with high-resolution microscopy
on normal and tumor cells.
Most importantly, we aim to understand how the spatial distribution
of chromosomes and genes is related to genome function. In this
regard, we are currently investigating the “role of the nucleolus on
the functional organization of Pol II dependent genes” and the
“Genome response to signalization events mediated by integrins”.
The nucleolus is the most prominent compartment of the nucleus,
where ribosomal genes are transcribed. We ask whether its activity
influences the spatial and functional organization of non-ribosomal
genes. To address this question we perform expression analysis of
genes mapping to chromosomes that harbour NOR, as well as
NOR-negative chromosomes, and RNA-FISH combined with nucleolus
immunostaining of nucleolar proteins to obtain single
cell expression profiles and in situ-loci mapping of genes
simultaneously. Since genomic events are also elicited by processes
in the extracellular microenvironment, we also study the organizational
changes of the genome associated with signalling events mediated
by cell-surface proteins. More specifically we wish to learn the nature
of the nuclear changes, and how integrins-mediated signalling
participates in the spatial genome reorganization during invasion
and metastasis.
Collaborations· Dr Alicia Lorenti (Laboratory of Tissue Engineering, University Hospital,
Austral University, Buenos Aires, Argentina).
· Dr África García-Orad (Dept. of Genetics, Universidad del País Vasco
UPV/EHU, Bizkaia, Spain).
· Dr María Luz Martínez-Chantar & Dr José M Mato (Metabolomics
Unit, CIC bioGUNE, Bizkaia, Spain).
· Dr Federico Garrido (Dept. of Clinical Chemistry & Immunology,
University Hospital Virgen de las Nieves, Granada, Spain).
Selected Publications1. Calvo A, Perez-Stable C, Segura V, Catena R, Garuceaga E, Nquewa P,
Blanco D, Parada LA, Green F. Molecular characterization of the
FG/Tag transgenic mouse model of hormone refractory prostate
cancer: comparison to human prostate cancer. The Prostate (2009
in press).
2. Royo F, Paz N, Espinosa L, Vellón L, Parada LA. Spatial link between
nucleoli and expression of the Zac1 gene. Chromosoma. Epub
DOI10.1007/s00412-009-0229-1 (2009).
3. Parada LA. Interphase genome organization and cancer.
Chromosome Research 17: 18-20 (2009).
4. Parada LA. Genome reorganization during invasive cell growth. Atlas
Genet Cytogenet Oncol Haematol, 12: 1-81 (2008).
5. Vellón L, Espinosa L, Royo F, Parada LA. α5β1 integrin-emanating
signals remodel nuclear architecture through the activation of
ERK1/2 and p38a MAPKs during invasive cell growth. Eur. J. Cancer
6: 36 (2008).
Lab. 3Luis Parada
Principal Investigator
Amaia ZabalaTechnician
Nerea PazPhD Student
Lab Members
Félix RoyoPostdoctoralResearcherCIBERehd Fellow Member
Luciano VellónPostdoctoralResearcher
Low oxygen availability or hypoxia is associated with several
physiopathological processes, like ischemia and cancer. This is why
the manipulation of the hypoxia-signalling cascade (by activating
and/or inhibiting) appears to be a very interesting therapeutic
approach. However, in order to do that, it is necessary to precisely
elucidate this signalling pathway and particularly, the mechanisms
regulating the α subunit of the Hypoxia Inducible Factor (HIF). Indeed,
HIFα is crucial in the hypoxia signalling pathway and the regulation
of its stability, the limiting step of this cascade.
HIFα stability is regulated by the PHDs (HIF Prolyl Hydroxylases or
Prolyl Hydroxylases Domain containing proteins). These enzymes
hydroxylate HIFα by using oxygen as a co-substrate and thus act as
veritable oxygen “sensors”. Three PHD isoforms have been identified:
PHD1, 2 and 3. The three isoforms are ubiquitously expressed but
their relative expression levels and localization are different. These
isoforms are able to hydroxylate HIFα in vitro, but our previous results
have shown that in cellulo, PHD2 plays a central and unique role in
well-oxygenated cells, whereas PHD1 and PHD3 only contribute to
the regulation of HIFα stability upon chronic hypoxia.
The aim of our group is to elucidate the PHDs regulatory mechanisms
and their physiological importance. We are planning to: i) study the
contribution of post-translational modifications like hydroxylation,
phosphorylation, acetylation, ubiquitination or sumoylation; ii) identify
new actors implicated in this regulatory pathway by performing a
high-throughput RNAi screening; iii) explore the impact of these new
actors on tumour growth and metastasis as well as in different
ischemia-models. This project will allow us to improve our basic
understanding of the hypoxia-signalling cascade and also to identify
new therapeutics targets in the pathologies in which hypoxia is
implicated.
The most important current projects
• Cascada de señalización activada por la hipoxia y cáncer
(SAF 2007-64597).
• Integration of Novel Nanoparticle based Technology for
Therapeutics and Diagnosis of different types of cancer;
NANOTHER (NMP4-LA-2008-213631).
Collaborations· Dr Sebastien Lecommandoux (LCPO-UMR5629-ENSCPB,
Bordeaux, France).
· Dr Javier Oliver (CSIC, Granada, Spain).
· Dr Alberto Pascual/José López-Barneo (IBiS, Sevilla, Spain).
· Dr Andrea Pichler (Max F. Perutz Laboratories, Vienna, Austria).
· Dr Tomás Santalucía/Anna Serra (IIBB-CSIC/IDIBAPS, Barcelona, Spain).
· Bioftalmik (Derio, Bizkaia, Spain).
· Colorobbia Italia Spa (Sovigliana, Vinci, Italy).
Selected Publications1. Loinard C, Ginouvès A, Vilar J, Cochain C, Zouggari Y, Recalde A,
Duriez M, Lévy B, Pouysségur J, Berra E, Silvestre JS. Inhibition of Prolyl
Hydroxylase Domain Proteins Promotes Therapeutic
Revascularization. Circulation, 120(1):50-59 (2009).
2. Ginouvès A, Ilc K, Macías N, Pouysségur J, Berra E. PHDs
overactivation during chronic hypoxia “desensitizes” HIFα and
protects cells from necrosis. Proc. Natl. Acad. Sci. USA 105: 4745-4750
(2008).
3. Trastour C, Benizri E, Ettore F, Ramaioli A., Chamorey E, Pouysségur
J, Berra E. HIF-1alpha and CA IX staining in invasive breast
carcinomas: Prognosis and treatment outcome. Int J Cancer,
120: 1443-1450 (2007).
Edurne Berra
Principal Investigator
Lab. 4
Analía NúñezO’MaraPhD Student
Francisco RGonzález-PachecoPostdoctoralResearcher
Nuria MacíasTechnician
Sara PozoTechnician
4. Berra E, Ginouvès A, Pouyssegur J. The hypoxia-inducible factor
hydroxylases bring fresh air into hypoxia signalling. EMBO Rep.
7: 41-45 (2006).
5. Berra E, Benizri E, Ginouvès A, Volmat V, Roux D, Pouysségur J. HIF
prolyl hydroxylase 2 is the key oxygen sensor setting low steady-
state levels of HIF-1alpha in normoxia. EMBO J. 22: 4082-4090 (2003).
Lab Members
STRUCTURALBIOLOGYUNIT
Structural Biology investigates the relationship
between structure and function of biological
macromolecules.
All cellular processes are maintained and regulated by biological
macromolecules. Structural Biology studies the relationship
between the three-dimensional structure of such molecules
and their specific function. The aim is to understand their role
in cellular pathways crucial to life. The aim of our unit is to
elucidate the three-dimensional structure of enzymes, proteins,
nucleic acids, as well as their complexes.
We try to understand the structural basis of biological processes
such as signal transduction, bacterial pathogenesis or gene
expression.
To this end we make use of biophysical techniques such as
Macromolecular Crystallography, Nuclear Magnetic Resonance,
Cryo-Electron Microscopy and Bioinformatic techniques.
STRUCTURALBIOLOGYUNIT
The laboratory is basically focused on two different projects. The first
one aims to understand how “cystathionine β-synthase (CBS) domains”
regulate the activity of their target proteins upon binding of different
ligands such as adenosyl groups or ions. The “CBS domain” proteins
comprise a large superfamily of evolutionarily-conserved proteins
which are present in all kingdoms of life. Mutations within these
motifs cause several hereditary diseases in humans, such as
homocystinuria, autosomic retinitis pigmentosa, myotonia congenital,
idyopatic epilepsy or hypercalciuric nephrolytiasis, among others.
Thus, they can be considered as promising targets for the development
of novel drugs. CBS domains are unusually abundant in archaea.
Organisms such as the hyperthermophile Methanococcus jannaschii
offer an excellent model for the characterization of the adenosyl
binding site of these proteins.
The second project is part of the CONSOLIDER program of the Spanish
Ion Channel Initiative, a multidisciplinar and cooperative initiative
aiming to understand the structure-function relationship in ionic
channels, headed by Prof. Antonio Ferrer Montiel from the University
Miguel Hernández in Elche, Spain. My group is involved in the 3D-
structure determination of selected targets using crystallographic
approaches.
Collaborations· Dr Sung-Hou Kim (University of California, Berkeley, CA, USA).
· Dr Liang Tong (Columbia University, New York, NY, USA).
· Dr Regine Herbst Irmer (Goteborg University, Goteborg, Germany).
· Dr George Sheldrick (Goteborg University, Germany).
· Dr Henri Blehaut (Institut Jerome Lejeune, Paris, France).
Alfonso Martínez de la Cruz
Principal Investigator
Lab. 1· Dr Martín Martínez-Ripoll (Instituto Rocasolano, CSIC, Madrid, Spain).
· Dr Armando Albert (Instituto Rocasolano, CSIC, Madrid, Spain).
· Dr Antonio Ferrer Montiel (Universidad Miguel Hernández,
Elche, Alicante, Spain).
· Dr José Luis Neira Faleiro (Universidad Miguel Hernández,
Elche, Alicante, Spain).
· Dr José Antonio Encinar Hidalgo (Universidad Miguel Hernández,
Elche, Alicante, Spain).
· Dr Jesús Prieto (CNIO, Madrid, Spain).
· Dr Javier Gómez (Universidad de Zaragoza, Zaragoza, Spain).
· Dr José Andrés Hernández (Universidad del País Vasco, UPV/EHU,
Bizkaia, Spain).
· Dr María Luz Martínez Chantar (CIC bioGUNE, Bizkaia, Spain).
· Dr José M Mato (CIC bioGUNE, Bizkaia, Spain).
Selected Publications1. Gómez García I, Kortázar D, Oyenarte I, Mato JM, Martínez-Chantar
ML, Martínez-Cruz LA. Purification, crystallization and preliminary
crystallographic analysis of protein MJ1225 from Methanocaldo-
coccus jannaschii, a putative archaeal homologue of gamma-AMPK.
Acta Crystallogr Sect F Struct Biol Cryst Commun. 65, 813-817 (2009).
2. Martínez-Cruz LA, Encinar JA, Kortazar D, Prieto J, Gómez J,
Fernández-Millán P, Lucas M, Astigarraga E, Fernández JA, Martínez-
Chantar ML, Mato JM and Neira JL. The CBS-domain protein MJ0729
of Methanococcus jannaschii is a thermostable protein with a pH-
dependent self-oligomerization. Biochemistry 48 (12):2766-2776 (2009).
3. Lucas M, Kortazar D, Astigarraga E, Fernández JA, Mato JM, Martínez-
Chantar ML, Martínez-Cruz LA. Purification, crystallization and
preliminary X-ray diffraction analysis of the CBS-domain pair from
the Methanococcus jannaschii protein MJ0100. Acta Crystallogr Sect
F Struct Biol Cryst Commun. 64 (10):936-941 (2008).
4. Fernández-Millán P, Kortazar D, Lucas M, Martínez-Chantar ML,
Astigarraga E, Fernández JA, Sabas O, Albert A, Mato JM, Martínez-
Cruz LA. Crystallization and preliminary crystallographic analysis of
merohedrally twinned crystals of MJ0729, a CBS-domain protein from
Methanococcus jannaschii. Acta Crystallogr Sect F Struct Biol Cryst
Commun. 64 (7):605-6 09 (2008).
Iker OyenarteTechnician
InmaculadaGómez García
PostdoctoralResearcher
Lab Members
Protein complexes of diverse nature are main subjects in our
crystallographic projects. We aim to understand if the knowledge of
structural principles of a biological intermolecular recognition can
be exploited to control and pharmacologically modulate protein
specificity. We focus our efforts on human neurodegenerative diseases,
and currently study complexes with RNA in project: “Structural Basis
for Suppression of Human Trinucleotide Repeat Expansion Diseases
(TREDs) ”and complexes with glycolipids in project: “ Molecular Basis
for Manipulating the Selectivity of Glycolipid Transfer”.
We are currently working on the two main projects:
• “Structural Basis for Suppression of Human Trinucleotide Repeat
Expansion Diseases”. Expanded tracts of repeated triplet sequences
in DNA cause many muscle- and neurodegenerative diseases. Our
central hypothesis [4] is that the mechanism of pathogenesis involves
a RNA interference pathway, which could be inhibited by means of
a viral suppressor of RNA interference p19. The protein p19 is known
to bind to small interfering RNAs (siRNAs) in a sequence non-specific
manner [6]. Our goal is to identify the p19 mutations, which make it
disease-repeat specific. We use the X-ray crystallographic approaches
to elucidate the structural principles for manipulating the p19/siRNA
binding specificity.
• “Molecular Basis for Manipulating the Selectivity of Glycolipid
Transfer”. Membrane lipids are increasingly being recognized as
regulators of numerous cellular processes. Much attention is focused
on the mechanisms by which cells impose selectivity and directionality
on lipid movement. Glycosphingolipids (GSLs), key regulators of
cellular differentiation, growth, development, and apoptosis, are
synthesized in the Golgi, and delivered to others membranes by both
Lucy Malinina
Principal Investigator
Lab. 2vesicular and non-vesicular mediated pathways. Glycolipid transfer
proteins (GLTPs) are small, soluble, and ubiquitous proteins that
selectively accelerate the intermembrane transfer of glycolipids.
The preliminary structural insights suggest a strict specificity of GLTP
for glycolipids, and the existence of a concerted sequence of events
during GSL transfer to/from membranes [2-3,5]. Our intention is
“to evolve” artificial GLTP species capable of distinguishing sugar
headgroups and lipid chain structures.
Collaborations· Dr Rhoderick E Brown (The Hormel Institute, Austin MN, USA).
· Dr Alexander Popov (ESRF, Grenoble, France).
· Dr Dinshaw J Patel (MSKCC, New York NY, USA).
Selected Publications1. Rechkoblit O, Malinina L, Cheng Y, Geacintov NE, Broyde S, Patel
DJ. Impact of Conformational Heterogeneity of OxoG Lesions and
Their Pairing Partners on Bypass Fidelity by Y Family Polymerases.
Structure.17:725-736 (2009).
2. Zhai X, Malakhova ML, Pike HM, Benson LM, Bergen HR 3rd, Sugár
IP, Malinina L, Patel DJ, Brown RE. Glycolipid Acquisition by Human
Glycolipid Transfer Protein Dramatically Alters Intrinsic Tryptophan
Fluorescence: INSIGHTS INTO GLYCOLIPID BINDING AFFINITY. J Biol
Chem. 284:13620-13628 (2009).
3. Malinina L, Malakhova ML, Kanak A, Lu M, Abagyan R, Brown RE
and Patel DJ. The liganding of glycolipid transfer protein is controlled
by glycolipid acyl structure. PLOS Biol. 4:e362 (2006).
4. Malinina L. Possible involvement of the RNAi pathway in trinucleotide
repeat expansion diseases. J. Biol. Struct. & Dynamics. 23:233-236 (2005).
5. Malinina L, Malakhova ML, Teplov A, Brown RE, Patel DJ. Structural
basis of glycosphingolipid transfer specificity. Nature. 430:1048-1053 (2004).
JevgeniaTamjarPhD Student
ElizavetaKatorchaPhD Student
ValeriyaSamyginaPostdoctoralResearcher
Borja OchoaDe EribeTechnician
Sandra DelgadoTechnician
Lab Members
Our research interest is focused on intracellular trafficking processes.
Eukaryotic cells have elaborate mechanisms of protein transport
through vesicular trafficking.
The Golgi is the major compartment at which different sorting
pathways diverge. Here, proteins undergo final modifications before
being directed into a variety of carrier vesicles for transport to the
cell surface, endosomal compartments or lysosomes. Vesicle targeting
and fusing with an acceptor membrane are regulated by a variety of
integral and peripheral membrane proteins that are highly conserved.
While fusion between vesicles is critical in pairing of integral membrane
SNARE proteins, peripheral multi-protein tethering complexes act
upstream by selecting and tethering target membranes in long-range
interaction.
My current research is focused on developing an understanding, on
the atomic level, of how tethering complexes contribute to specificity
of membrane fusion by recognizing vesicle features in both donor
and acceptor membranes.
To pursue these studies I use X-ray crystallography of protein
complexes in combination with cell biology and biochemistry.
Since vesicle tethering events play key roles in intracellular network,
studying tethering factors from a structural viewpoint represents a
crucial stage in understanding how protein-protein recognition and
protein-membrane interactions regulate the correct vesicle targets.
Many clinical manifestations of diseases are related to malfunction
or hijacking of these pathways, therefore detailed knowledge of these
interactions is necessary to search for possible therapies.
Aitor Hierro
Principal Investigator
Lab. 3Collaborations· Dr Juan S. Bonifacino (National Institute of Child Health and Human
Development, Bethesda, MD, USA).
Selected Publications1. Hierro A*, Rojas AL*, Rojas R, Murthy N, Effantin G, Kajava AV, Steven
AC, Bonifacino JS, Hurley JH. Functional architecture of the retromer
cargo-recognition complex. Nature. 25; 449(7165):1063-1067 Epub
2007 Sep 23 (2007).
2. Kostelansky MS, Sun J, Lee S, Kim J, Ghirlando R, Hierro A, Emr SD,
Hurley JH. Structural and functional organization of the ESCRT-I
trafficking complex. Cell. 7;125(1):113-126 (2006).
3. Kim J, Sitaraman S, Hierro A, Beach BM, Odorizzi G, Hurley JH.
Structural basis for endosomal targeting by the Bro1 domain. Dev
Cell. 8(6):937-947 (2005).
4. Hierro A, Sun J, Rusnak AS, Kim J, Prag G, Emr SD, Hurley JH. Structure
of the ESCRT-II endosomal trafficking complex. Nature 9;431
(7005):221-225 Epub 2004 Aug 25 (2004).
* These authors contributed equally.
Lab MembersAnderVidaurrazagaTechnician
María SerranoPostdoctoralResearcher
GuillermoAbascalPhD Student
Igor TascónPhD Student
Melisa LázaroTechnician
We observe working molecular motors to understand their
functioning. By means of cryo-electron microscopy we can obtain
3D maps of such motors in close to physiological conditions, even
within the cells. Our aim is to describe conformational changes of
macromolecules during their performance.
We focus on motors involved in universal biological functions where
interactions between protein and nucleic acids are essential. Structural
studies of ribosomes during translation allow the understanding of
the mechanisms which govern protein synthesis. In this line,
interactions with translation factors and interference by several
antibiotics in the process are especially important. Another working
interest concentrates on the structural characterization of p53 tumor
suppressor. This protein works as transcription factor of genes involved
in cell cycle control in vertebrates and hence functions as a tumor
suppressor. The protein has been found mutated in about half of
human tumors. We are interested in the structure of p53 tetramers
and their interaction with DNA and other cell cycle controlling proteins.
Collaborations· Dr Alan Fresht (Medical Research Council; University of
Cambridge, Cambridge, UK).
· Dr Marina V. Rodnina (Max Planck Institute for Biophysical
Chemistry, Göttingen, Germany).
· Dr Liang Tong (Columbia University, NY, USA).
Selected Publications1. Yu L, Xiang S, Lasso G, Gil D, Valle M, Tong L. A symmetrical tetramer
for S. aureus pyruvate carboxylase in complex with coenzyme A.
Structure 17 (6): 823-832 (2009).
Mikel Valle
Principal Investigator
Lab. 42. Scheres SH, Valle M, Grpb P, Nogales E, Carazo JM. Maximum
likelihood refinement of electron microsocpy data with normalization
errors. J Struct Biology; 166: 234-240 (2009).
3. Conde-Vancells J, Rodríguez-Suárez E, Embade N, Gil D, Matthiesen
R, Valle M, Elortza F, Lu SC, Mato JM, Falcón-Pérez JM. Characterization
and Comprehensive Proteome Profiling of Exosomes Secreted by
Hepatocytes. J Proteome Res. 7(12):5157-5166 (2008).
4. Julián P, Konevega AL, Scheres SH, Lázaro M, Gil D, Wintermeyer W,
Rodnina MV, Valle M. Structure of ratcheted ribosomes with tRNAs in
hybrid states. Proc Natl Acad Sci USA. 4;105(44):16924-16927 (2008).
5. Tidow H, Melero R, Mylonas E, Freund SM, Grossmann JG, Carazo
JM, Svergun DI, Valle M, Fersht AR. Quaternary structures of tumor
suppressor p53 and a specific p53 DNA complex. Proc Natl Acad Sci
USA. 24;104(30):12324-12329 (2007).
Lab Members
Gorka LassoPostdoctoralResearcher
Patricia JuliánPhD Student
Xabier AgirrezabalaPostdoctoralResearcher
Collaborations· Dr Dennis H Bamford (Finnish Centre of Excellence in Virus Research,
University of Helsinki, Finland).
· Dr Stephen D Bell (Sir William Dunn School of Pathology, University
of Oxford, UK).
Selected Publications1. Korkhin Y, Unligil UM, Littlefield O, Nelson PJ, Stuart DI, Sigler PB,
Bell SD and Abrescia, NGA. Evolution of Complex RNA Polymerases:
the Complete Archaeal RNA Polymerase Structure. Plos Biology 7(5):
e1000102. doi:10.1371/Journal.Pbio.1000102 (2009).
2. Kadlec J, Loureiro S, Abrescia NG, Stuart DI, and Jones IM. The
postfusion structure of baculovirus gp64 supports a unified view of
viral fusion machines. Nat. Struct. Mol. Biol. 15, 1024-1030 (2008).
3. Abrescia NG, Grimes JM, Kivelä HM, Assenberg R, Sutton G, Butcher
SJ, Bamford JKH., Bamford DH, Stuart DI. Insights into virus evolution
and membrane biogenesis from the structure of the marine lipid-
containing bacteriophage PM2. Mol. Cell. 5, 749-761 (2008).
4. Abrescia NG, Cockburn JJB, Grimes JM, Sutton GC, Diprose JM,
Butcher , Fuller SD, San Martín C, Burnett RM, Stuart DI, Bamford DH,
Bamford JKH. Insights into assembly from structural analysis of
bacteriophage PRD1. Nature 432, 68-74 (2004).
5. Cockburn JJB, Abrescia NG, Grimes JM, Bamford JKH, Benevides J,
Thomas GJr, Bamford DH, Stuart DI. Membrane structure and
interactions with protein and DNA in bacteriophage PRD1. Nature,
432, 122-125 (2004).
Lab Members
Biological complexity is often associated with processes which require
highly accurate and regulated protein interactions. Examples of such
complexity can be found in the assembly pathway of viruses or in
the molecular mechanism of “gene expression”. Our research aims
to understand how large multi-component proteins assemble,
function and interact in the cellular context.
One line of investigation is directed to the understanding of virus
structures, their assembly principles and to the virus-cell recognition
mechanisms. Indeed, viruses represent a source of wonder as
miniaturized entities that permeate and cross-interact with the entire
biosphere and are by far the most numerous organisms on earth.
Some of them are, however, pathogens and represent a threat to
human and animal health. The understanding of virus morphogenesis
and virus-host recognition mechanisms is fundamental in the
development of antiviral drugs. The second line of research is focused
on the elucidation of transcription initiation and regulation using
Archaea as a model system for Eukarya. Transcription can be divided
into three major steps: Initiation, Transcription/Elongation and
Termination. Initiation and Termination are the less understood
processes but relevant in many associated gene disorders.
Research in our group is focused on the structural analysis by cryo-
electron microscopy and crystallography techniques of biomedically
relevant non-infectious subviral particles (SVPs) of Flaviviruses and of
the pre-initiation-complex (PIC) of the archaeal RNA polymerase
transcription machinery.
Nicola G A Abrescia
Principal InvestigatorIkerbasque Research Professor
Lab. 5
Marina OndivielaTechnician
Bibiana PeraltaPostdoctoralResearcher
Magda WojtasPhD Student
Mutations in the primary sequence of enzymes are often ultimately
responsible for a large number of autosomal diseases. In our laboratory
we pursue the structural characterization of two enzymes involved
in heme group biosynthesis: uroporphyrinogen III synthase and
porphobilinogen deaminase. A decrease in their catalytic activity
results in the outbreak of a pathology called porphyria. Porphyria has
a low statistical incidence but very acute symptoms, usually inversely
proportional to the residual catalytic activity. This activity loss can be
produced by a perturbation in the active centre, a conformational
change or an overall thermodynamic destabilization of the enzyme.
A detailed structural characterization can provide useful therapeutical
and diagnostic information. We make use of nuclear magnetic
resonance (NMR) to understand the relationship between porphyria
and the structural determinants of the heme group biosynthesis.
The large catalytic efficiency and the exquisite enantioselectivity of
an enzyme has been employed in some industrial processes to
upgrade their properties towards an environmentally-friendly process.
However, large scale industrial implementation of biotechnological
reactions is often limited by the marginal stability of the enzyme in
the reactor conditions. In our laboratory we employ NMR and circular
dichroism to investigate the effect of external crowding agents to
improve the activity and stability for several enzymes. Furthermore,
we are interested in the relationship between the cosolute induced
stability changes and a rational modification of the protein surface
by means of site directed mutagenesis.
Proteins from halophilic organisms function in extreme saline
conditions and have evolved to remain folded at very high ionic
strengths. The surfaces of halophilic proteins show a biased aminoacid
composition with a high prevalence of aspartic and glutamic acids, a
low frequency of lysine and a high occurrence of aminoacids with small
side chains. In our laboratory we are investigating the mechanism for
protein haloadaptation by a combined use of site directed mutagenesis
and high-resolution NMR spectroscopy.
Collaborations· Dr Gloria del Solar (Centro de Investigaciones Biológicas,
Madrid, Spain).
· Dr Javier Sancho (Unidad de Biofísica BIFI, Zaragoza, Spain).
· Dr Miquel Pons (Parc Científic de Barcelona, Barcelona, Spain).
Selected Publications1. Tadeo X, López-Méndez B, Castaño D, Trigueros T, Millet O. Protein
stabilization and the Hofmeister effect: the role of hydrophobic solvation.
Biophysical Journal, 97, 2595-2603 (2009).
2. Fortian A, Castaño D, Ortega G, Laín A, Pons M, Millet O.
Uroporphyrinogen III synthase mutations related to congenital
erythropoietic porphyria identify a key helix for protein stability.
Biochemistry 20;48(2):454-461 (2009).
3. Tadeo X, Castaño D, Millet O. Anion modulation of the 1H/2H exchange
rates in backbone amide protons monitored by NMR spectroscopy. Protein
Science, 33, 2733-2740 (2007).
4. Blobel J, Schmidl S, Vidal D, Nisius L, Bernadó P, Millet O, Brunner E,
Pons M. Protein tyrosine phosphatase oligomerization studied by a
combination of 15N NMR relaxation and 129Xe NMR. Effect of buffer
containing arginine and glutamic acid. Journal of the American Chemical
Society 129, 5946-5953 (2007).
5. Tadeo X, Pons M, Millet O. Influence of the Hofmeister Anions on Protein
Stability As Studied by Thermal Denaturation and Chemical Shift
Perturbation. Biochemistry, 46, 917-923 (2007).
Oscar Millet
Principal Investigator
Lab. 7
Lab Members
Xabier TadeoPhD Student
David CastañoPhD Student
Blanca LópezMéndezPostdoctoralResearcher
Ana LaínTechnician
Our main research interest is the structural characterization of proteins
and their interactions with other molecules relevant to chromatin
remodeling, DNA replication and repair, and cell adhesion. Our main
tool is Nuclear Magnetic Resonance spectroscopy; we also use other
biophysical techniques.
ING4, a member of the Inhibitor of Growth family of tumor suppressor
proteins, contains a C-terminal Plant Homeo domain (PHD). The PHD
of ING4 binds to histone methylated tails and is involved in
transcription activation, through its interaction with the Histone
Acetyl transferase complex HBO1. The structure and dynamics of
ING4-PHD bound to histone 3 trimethylated at Lys4 has been
determined, and the specificity of binding to different methylated
histone fragments in solution has been analyzed. We found that
binding affects the PHD backbone dynamics, in contrast to previous
assumptions of histone binding being made by static protein modules.
The specificity for the methylated histone tail recognition is entropy
driven, in contrast to chromodomains. Our results highlight the
versatility of PHD fingers as readers of the histone code. We are
currently studying how the crowded, inner macromolecular
environment of cells affects the recognition of methylated histones.
Gadd45α (Growth Arrest and DNA damage-inducible gene) is a
nuclear protein transcriptionally regulated by the tumor suppressor
p53. The interactions of Gadd45α with other proteins play a central
role in DNA repair, cell cycle control and apoptosis. The solution
structure of human Gadd45α shows a α/β fold with a five stranded
mixed β-sheet at the core and five helices surrounding it. We are
currently investigating the interaction of GADD45α with PCNA
(Proliferating Cellular Nuclear Antigen) and other proteins involved
in cell cycle control and DNA repair.
Francisco Blanco
Principal InvestigatorIkerbasque Research Professor
Lab. 8Meganucleases recognize long DNA sequences (between 14 and
40 bp) and produce double strand breaks at single sites in whole
genomes. Engineered meganucleases can be used to induce
endogenous homologous recombination and repair defective genes
ex vivo without detectable genotoxicity. We are characterizing the
structure-function relationships of several of these highly specific
nucleases of biomedical interest.
We have characterized the binding of a group of small molecules
designed to compete for the binding to the I-domain of the integrin
lymphocyte function-associated antigen-1 (LFA-1) to the intercell
adhesion molecule-1 (ICAM-1). These interactions play a key role in
autoimmune diseases and cancer. We have found that these ligands
bind to the I-domain of LFA-1, but not to the MIDAS (metal ion
dependent adhesion site), the site of ICAM-1 binding. They bind
instead to the IDAS (I-domain allosteric site), suggesting that they
may act as allosteric inhibitors, in a way similar to lovastatin.
Collaborations· Dr Guillermo Montoya (CNIO, Madrid, Spain).
· Dr Frédéric Pâques (Cellectis SA, Romainville, France).
· Dr Fernando Cossío (Universidad del País Vasco UPV/EHU, Gipuzkoa,
Spain).
· Dr Ignacio Palmero (IIB-UAM-CSIC, Madrid, Spain).
· Dr Irene Luque (UG, Granada, Spain).
· Dr Ramón Campos-Olivas (CNIO, Madrid, Spain).
Selected Publications1. Palacios A, Muñoz IG, Pantoja-Uceda D, Marcaida MJ, Torres D,
Martín-García JM, Luque I, Montoya G, Blanco FJ. Molecular basis of
histone H3K4Me3 recognition by ING4. Journal of Biological Chemistry
283: 15946-15964 (2008).
2. Zimmerman T, Blanco FJ. Inhibitors targeting the LFA-1/ICAM-1 cell-
adhesion interaction: design and mechanism of action. Current
Pharmaceutical Design 14: 2128-2139 (2008).
SimoneCulurgionePhD Student
Alfredo De BiasioPostdoctoralResearcher
3. Sánchez R, Pantoja-Uceda D, Torres D, Prieto J, Campos-Olivas R,
Blanco FJ. NMR assignment and secondary structure of human growth
arrest and DNA damage protein Gadd45α. Biomolecular NMR
Assignments 2: 245-247 (2008).
4. Redondo P, Prieto J, Muñoz IG, Alibés A, Stricher F, Serrano L,
Cabaniols JP, Daboussi F, Arnould S, Pérez C, Duchateau P, Pâques F,
Blanco FJ, Montoya G. Molecular basis of xeroderma pigmentosum
group C DNA recognition and cleavage by engineered meganucleases.
Nature 456:107-111 (2008).
Lab Members
Maider VillateTechnician
Nekane MerinoTechnician
John AlexanderRodríguezBuitragoPhD Student
TECHNOLOGYPLATFORMS
STRUCTURALBIOLOGYPLATFORMS
Structural biology is a highly interactive and versatile
discipline dedicated to elucidating the function of
biomolecules by high-resolution analysis of their
3-dimensional structure. This may furthermore
include studies of molecular dynamics and
interactions, also with atomic resolution.
Structural biology relies on the combination and cooperation of
several complementary techniques: specialised biochemistry to
provide for the target molecules in the required purity, quantity
and with possible modifications; NMR spectroscopy, X-ray
crystallography and electron microscopy as the experimental core
STRUCTURALBIOLOGYPLATFORMS
techniques for structure analysis up to atomic resolution;
computational bioinformatics methods for structure prediction,
calculation and analysis; and various auxiliary biophysical methods
to further characterise the target molecules and complement the
structural information.
This multi-disciplinary approach can provide for a fundamental
understanding of complex biological phenomena at molecular
level. The resulting data on atomic distances, molecular shape,
dynamics, charge distribution, interaction, etc., allow for a
comprehensive view on molecular mechanisms of action.
Such knowledge is of basic importance for various fields of research,
and particularly for rational drug development.
Atomic characterization of macromolecules and their interactions
with macro and small molecules is the cornerstone of understanding
many biological processes. X-ray crystallography is currently the most
powerful technique to study the structure of a wide range of biological
molecules such as nucleic acids, proteins, macromolecular complexes
and viruses.
CIC bioGUNE enjoys state-of-the-art X-ray crystallography facilities.
The platform is equipped with a X8-PROTEUM system (BRUKER) with
two detectors and a cryosystem for data collection, liquid handling
(TECAN), Crystallization robot (MOSQUITO) and a Crystal Farm (BRUKER)
image analysis platform. Other complementary techniques as Circular
Dichroism and Dynamic Light Scattering are also available. At the
Macromolecular Crystallography Platform we provide user support
from sample preparation to structure determination.
Selected Publications1. Golubev A M, Rojas AL, Nascimento AS, Bleicher L, Kulminskaya AA,
Eneyskaya EV, Polikarpov I. Crystallization and preliminary crystallographic
analysis of laminarinase from Rhodothermus marinus: a case of
pseudomerohedral twinning. Protein Pept Lett, 15(10): 1142-1144 (2008).
2. Rojas R, Vlijmen TV, Mardones G, Prabhu Y, Rojas AL, et al. Regulation
of Retromer Recruitment to Endosomes by Sequential Action of Rab5 and
Rab7. J Cell Biol ,183(3):513-526 (2008).
Adriana L RojasPlatform Manager
MACROMOLECULARCRYSTALLOGRAPHYPLATFORM
3. Hierro* A, Rojas* AL, Rojas R, et al. Functional Arquitecture of the retromer
cargo recognition complex. Nature, 449 (7165): 1063-1067 (2007).
4. Rojas AL, Fischer H, Eneiskaya EV, et al. Structural Insights into the beta-
Xylosidase from Trichoderma reesei Obtained by Synchrotron Small-Angle
X-ray Scattering and Circular Dichroism Spectroscopy. Biochemistry, 44:
15578-15584 (2005).
5. Nagem RPA, Ambrosio ALB, Rojas AL, et al. Getting the most of X-ray
home sources. Acta Crystallographica D. D61: 1022–1030 (2005).
* These authors contributed equally.
The mission of the Electron Microscopy Facility at CIC bioGUNE is to
offer state-of-the-art instrumentation, services and training for high-
resolution transmission electron microscopy to biomedical researchers.
To fulfil these goals, the Electron Microscopy Facility provides two
transmission electron microscopes, including a JEM-2200FS
transmission electron microscope equipped with a field emission
gun (FEG) and an in-column energy filter, as well as major auxiliary
equipment such as vitrification robots required for the preparation
and imaging of biological samples at cryogenic temperatures
(http://personal.cicbiogune.es/dcarton/).
This high-tech equipment allows us to make use of advanced methods
of image processing and computation to investigate at different
levels the biological complexity of large macromolecular structures
(c.f. ribosomes, virus-like-particles, etc.) by three-dimensional
reconstruction techniques.
Collaborations· Dr Mikel Valle (CIC bioGUNE, Bizkaia, Spain).
· Dr Nicola Abrescia (CIC bioGUNE, Bizkaia, Spain).
· Dr Juan M Falcón (CIC bioGUNE, Bizkaia, Spain).
· Dr Ilya Reviakine (CIC biomaGUNE, Gipuzkoa, Spain).
· Dr Itziar Alkorta (Universidad del País Vasco UPV/EHU, Bizkaia, Spain).
· Dr Arturo Muga (Universidad del País Vasco UPV/EHU, Bizkaia, Spain).
· Dr Diego M. A. Guérin (Universidad del País Vasco UPV/EHU, Bizkaia, Spain).
· Dr Juan Manuel González-Mañas (Universidad del País Vasco
UPV/EHU, Bizkaia, Spain).
· Dr África Barrientos (Midatech, Derio, Bizkaia, Spain).
· Dr Rubén Álvarez Rodríguez (BIOFORGE, Valladolid, Spain).
· Dr José Carlos Rodríguez Cabello (BIOFORGE, Valladolid, Spain).
· Dr María Moragues (NANOC LABEIN - Tecnalia, Derio, Bizkaia, Spain).
· Dr Yolanda de Miguel (NANOC LABEIN - Tecnalia, Derio,
Bizkaia, Spain).
· Dr Edurne Erkizia (NANOC LABEIN - Tecnalia, Derio, Bizkaia, Spain).
· Dr José Antonio Ibáñez (NANOC LABEIN - Tecnalia, Derio,
Bizkaia, Spain).
· Dr Sandra Rainieri (AZTI - Tecnalia / Food Research, Derio,
Bizkaia, Spain).
Selected Publications1. Yu L, Xiang S, Lasso G, Gil D, Valle M, Tong L. A symmetrical tetramer
for S. aureus pyruvate carboxylase in complex with coenzyme A.
Structure, 17 (6): 823-832 (2009).
2. Julián P, Konevega AL, Scheres SH, Lázaro M, Gil D, Wintermeyer W,
Rodnina MV, Valle M. Structure of ratcheted ribosomes with tRNAs in
hybrid states. Proc Natl Acad Sci USA, 105(44):16924-16927 (2008).
3. Conde-Vancells J, Rodríguez-Suárez E, Embade N, Gil D, Matthiesen
R, Valle M, Elortza F, Lu SC, Mato JM, Falcón-Pérez JM. Characterization
and Comprehensive Proteome Profiling of Exosomes Secreted by
Hepatocytes. J Proteome Res, 7, 12: 5157-5166 (2008).
David GilPlatform Manager
ELECTRONMICROSCOPYPLATFORM
The NMR equipment at CiC bioGUNE is highly complementary, and
ideally suited for a double-track strategy: a 600 MHz medium-field
spectrometer with flexible configuration and ample accessories allows
for a variety of highly specialised NMR experiments beyond standard
biomolecular applications; and a 800 MHz high-field spectrometer
with fixed configuration and a cryo-probe to run classical biomolecular
NMR applications with highest sensitivity. Both BRUKER spectrometers
are of the most modern AVANCE III generation.
To complement the modern NMR hardware, an ongoing project
of the NMR platform is the continuous optimisation of existing NMR
experiments with regard to user friendliness, robustness and maximum
sensitivity. Recent improvements have already yielded an average of
50% sensitivity gains with respect to conventional implementations
of NMR experiments. We are currently exploring the limits of these
sensitivity-enhancement schemes, and their broadness of application.
In collaboration with partners from the Max-Planck-Institutes
(Tuebingen), we are furthermore developing NMR methodology to
cleanse spectra from uninformative components or artifacts,
and to measure new NMR parameters required for a novel streamlined
protocol for fast protein structure analysis with highest resolution.
Exploiting the ample extra accessories available for the 600 MHz,
especially its set of dedicated probe-heads, we are also extending
Tammo DiercksPlatform Manager
NUCLEARMAGNETICRESONANCE(NMR)
the range of conventional biomolecular NMR applications to, e.g.,
study more exotic nuclei. In a collaboration project with partners
from the CIB (Madrid) and Ludwig-Maximilians-University (Munich)
we have, thus, developed a novel NMR approach to study
carbohydrate-protein interactions. This technique has already been
shown to yield unique new insight into binding kinetics and substrate
specificity, and is now being developed further and applied more
broadly.
Collaborations· Dr Hans-Joachim Gabius (Ludwig-Maximilians-Universitaet,
Muenchen, Germany).
· Dr Jesús Jiménez Barbero (Centro de Investigaciones Biológicas,
Madrid, Spain).
· Dr Murray Coles and Dr Vincent Truffault (Max-Planck Institute for
Developmental Biology, Tuebingen, Germany).
Selected Publications1. Diercks T, Ribeiro JP, Cañada FJ, André S, Jiménez-Barbero J, Gabius
H-J. Fluorinated Carbohydrates as Lectin Ligands: Versatile Sensors
in 19F-Detected Saturation Transfer Difference NMR Spectroscopy.
Chem. Eur. J. 15: 5666-5668 (2009).
2. Diercks T, AB E, Daniëls MA, de Jong, RN, Besseling R, Kaptein R,
Folkers GE. Solution Structure and Characterization of the DNA-Binding
Activity of the B3BP-Smr Domain. J. Mol. Biol. 383:1156-1170 (2008).
GENOMEANALYSISPLATFORM
The Genome Analysis Platform at CIC bioGUNE
offers services in the latest technologies for
high-throughput genome analysis.
GENOME ANALYSISPLATFORM
The national and international scientific communities can take
advantage of high-throughput genome analysis technologies offered
by Genome Analysis Platform at CIC bioGUNE:
* The BeadStation 500 GT/GX (Illumina, Inc., www.illumina.com), for
high-throughput standard and customized SNP genotyping, gene
expression and methylation analysis; and
* The Genome Analyzer (Illumina Inc., www.illumina.com), which
allows Sequencing-by-Synthesis (SBS) for multiple applications
including genome sequencing and re-sequencing, digital gene
expression (tag profiling and small-RNA discovery and analysis) and
in vivo protein-DNA interactions identification and quantification on
a genome-wide scale (ChiP-Seq methodology).
In addition to the technological set-up, several Bioinformatics tools
are being developed. Therefore, we can offer some assistance in the
designing of the customized SNP (for genotyping projects) or gene
panels (for differential expression projects) and in basic statistical
analyses of the resulting data.
Quotations for genotyping, transcriptomics, methylation analysis or
sequencing services can be requested at: "[email protected]" or
"http://genomics.cicbiogune.es/GAP/service".
Platform MembersAne FullaondoPlatformSpecialist
Naiara RodríguezEzpeletaPlatformSpecialist
Ewa Gubb *Technician
AintzaneGonzález LaheraTechnicianCIBERehd Fellow Member
Ana Mª AransayPlatform Manager
GENOME ANALYSISPLATFORM
* External
PROTEOMICS &METABOLOMICSPLATFORM
The proteomics and metabolomics platform is chiefly
focused on the analysis of proteins and metabolites
by mass spectrometry. This platform provides service
both to in-house and external research groups.
PROTEOMICS& METABOLOMICSPLATFORM
At the beginning of the XXI century, the biomedical research scenario
changed with the so called post-genomic era. Then, gene product
analysis, thus, protein analysis on a large scale became feasible.
The Proteomics platform provides protein identification and molecular
weight determination service by mass spectrometry (MS) using the
following equipment:
MALDI Platform:
A Proteineer DP robotic station for in-gel automatic digestion and
an Autoflex TOF/TOF smartbeam mass spectrometer (Bruker). Proteins
are identified by peptide mass fingerprinting and/or peptide fragment
fingerprinting.
Liquid chromatography tandem mass spectrometry systems:
Two nano flow liquid chromatography system are coupled to a
quadrupole time of flight hybrid instrument Q-TOF premier (Waters-
Micromass) and to an Orbitrap XL upgraded with the ETD module
(Thermo-Fisher), respectively. These high performance systems have
the latest features for optimal protein identification in complex protein
mixtures and for in depth protein post-translational modification
characterisation analysis.
Proteomics Core Facility works for the continuous development of
mass spectrometry based proteomic methods to better address
Felix ElortzaPlatform Manager
PROTEOMICS &METABOLOMICSPLATFORM
proteomic research related new challenges. Researchers at this
laboratory are actively involved in research projects such as HUPO´s
Human Liver Proteome Project. Different collaborative efforts are
carried out with groups from CIC bioGUNE, neighbouring proteomics
core facility in the UPV/EHU and also international laboratories.
With the aim of discovering new diagnostic biomarkers, the Proteomics
Platform works closely with the company OWL Genomics, whose
Metabolomics Platform is managed by Doctor Jonathan Barr,
responsible for metabolomics studies. OWL Genomics has established
a state-of-the-art mass spectrometry based metabolomics platform
ideally suited to studies in key areas such as biomarker discovery,
clinical studies, diagnostics and toxicology.
Mass spectrometry based metabolomics offers selective, sensitive
analyses with the potential to identify metabolites. The analytical
platform at OWL Genomics includes several liquid-chromatography
interfaced mass spectrometers:
UPLC TOF: This mass analyser delivers high full-scan sensitivity,
resolution, and exact mass measurements ideal for the high
throughput, selective analysis of hundreds to thousands of metabolites
found in biofluids and tissues.
UPLC Q-TOF: Possesses all the above features with the added benefits
of quadrupole precursor ion selection and controlled fragmentation
in a collision cell prior to TOF analysis. The unique design of this
instrument allows MS data to be captured with alternating low- and
high collision cell energy. This MSE approach can be used to obtain
both precursor and product ion information in the same analytical
run.
Selected Publications1. Casado-Vela J, Rodríguez-Suárez E, Iloro I, Ametzazurra A, Alkorta
N, García-Velasco JA, Matorras R, Prieto B, González S, Nagore D, Simón
L, Elortza F. Comprehensive proteomic analysis of human endometrial
fluid aspirate. Journal of Proteome Research 8, 10, 4622-4632 (2009).
Mikel AzkargortaTechnician
Juan CasadoPlatformSpecialist
2. Conde-Vancells J, Rodríguez-Suárez E, Embade N, Gil D, Matthiesen
R, Valle M, Elortza F, Lu SC, Mato JM, Falcón-Pérez JM. Characterization
and Comprehensive Proteome Profiling of Exosomes Secreted by
Hepatocytes. Journal of Proteome Research 7, 12 5157-5166 (2008).
3. Omaetxebarria MJ, Elortza F, Rodríguez-Suárez E, Aloria K,
Arizmendi JM, Jensen ON and Matthiesen R. Computational approach
for identification and characterization of gpi-anchored peptides in
proteomics experiments. Proteomics 7, 12, 1951-1960 (2007).
4. Elortza F, Mohammed S, Bunkenborg J, Foster LJ, Nühse TS,
Brodbeck U, Peck SC and Jensen ON. Modification-specific proteomics
of plasma membrane proteins: identification and characterization
of glycosylphosphatidylinositol-anchored proteins released upon
phospholipase D treatment. Journal of Proteome Research 5, 4,
935-943 (2006).
Platform Members
Ibon IloroPlatformSpecialist
Eva RodríguezSuárezPlatformSpecialist
Gene silencing by RNAi is ushering biological research
into a new age. Using the human genome sequence
and the ability of RNAi to systematically silence families
of genes or even all genes, we can expect to obtain a
functional genomic map that can give rise to novel
therapeutic approaches.
GENE SILENCINGPLATFORM
RNAi is an evolutionarily conserved, sequence-specific post-
transcriptional gene silencing mechanism induced by double stranded
RNA (dsRNA). The RNAi machinery can also be triggered by exogenous
delivery of dsRNAs providing an extremely powerful tool for genetic
analysis. Thus, gene silencing by RNAi is ushering biological research
in a new age. Using the human genome sequence and the ability of
RNAi to systematically silence families of genes or even all genes, we
can expect to obtain a functional genomic map that can give rise to
novel therapeutic approaches.
The GSP is a dedicated facility to develop and execute cell-based
screenings using RNAi with a dedicated staff to manage platform
resources and to help in assay development and analysis. The main
goal of the platform is to make RNAi-mediated gene silencing as
widely accessible as possible.
We are currently working with the human retroviral shRNAmir library
(developed in the Hannon-Elledge labs, Open Biosystems) offering
wide genome coverage, efficient silencing and flexible vector formats.
We also provide the Silencer® Drosophila RNAi Library distributed by
Ambion/Applied Biosystem. This library is a collection of 13.071 dsRNAs
targeting the best annotated Drosophila genome.
We facilitate in vitro and in vivo silencing of individual or families of
genes (sub-libraries) to elucidate their functions and also high-
throughput, high-content screening to identify new genes implicated
Edurne BerraPlatform Manager
GENE SILENCINGPLATFORM
Monika GonzálezLópezPostdoctoralResearcher
EncarnaciónPérez AndrésTechnician
in particular biological processes. We advise users on screen design
and can adapt our protocols (cellular models and biological assays)
to meet user needs: human, mouse, or Drosophila primary or tumor
cells, for the analysis of stem cell differentiation, tumor invasion, cellular
adhesion, angiogenesis, etc. The Platform is equipped with an
automated liquid handling system (Sciclone ALH3000), a robotic plate
delivery system (Twister II) and different peripheral systems: CO2
incubator with plate shuttling (Cytomat 2C), microplate reader (Synergy
HT), automated microscope and high-content analysis software
(ImageXpressMicro, MetaXpress, AcuityXpress, MDCShare data base).
Platform Members
RESEARCHSUPPORTUNITS
The CIC bioGUNE´s Animal Unit (AU) is an AAALAC
accredited facility which includes a Specific Pathogen
Free (SPF) area to house rodents from commercial
sources and to produce and keep some strains of
genetically engineered mice (GEM).
THE MAIN FUNCTIONS OF THE AU ARE:
• Covering the CIC bioGUNE user´s needs by providing them
with the assessment and equipment necessary to carry out
their research on laboratory animals.
• Providing the care and welfare of laboratory animals, and
carrying out periodic health monitoring.
• Ensuring observance of all legal and ethical standards
concerning the use of animals for research and other scientific
ends.
The AU works for the continuing improvement in their services
and also engages in the development of new services through
the collaboration with researchers from different areas of interest.
With this in mind, our main objective for the coming months is
focused on the use of ultrasounds (echography) to detect liver
lesions in murine models of steatosis and hepatic tumours. In
addition, preliminary echocardiography assays are being developed
in order to assess the heart function in new strains of GEM.
Selected Publications1. Varela-Rey M, Fernández-Ramos D, Martínez-López N, Embade N,
Gómez-Santos L, Vázquez-Chantada M, Rodríguez J, Luka Z, Wagner
C, Lu SC, Martínez-Chantar ML, Mato JM. Impaired Liver Regeneration
in Mice Lacking Glycine N-Methyltransferase. Hepatology 50(2):4443-
4452 (2009).
2. Martínez-Chantar ML, Vázquez-Chantada M, Ariz U, Martínez N,
Varela M, Luka Z, Capdevila A, Rodriguez J, Aransay AM, Matthiesen
R, Yang H, Calvisi DF, Esteller M, Fraga M, Lu SC, Wagner C, Mato JM.
Loss of the Glycine N-Methyltransferase Gene Leads to Steatosis and
Hepatocellular Carcinoma in Mice. Hepatology 47(4):1191-1199 (2008).
3. Rodríguez-Cuesta J, Vidal-Vanaclocha F, Mendoza L, Valcárcel M,
Gallot N, Martínez de Tejada G. Effect of asymptomatic natural
infections due to common mouse pathogens on the metastatic
progression of B16 murine melanoma in C57BL/6 mice. Clinical and
Experimental Metastasis 22(7):549-558 (2005).
ANIMALFACILITIES UNIT
Juan Rodríguez CuestaAnimal Unit Officer
Arantza PeñaTechnician
Virginia PérezLuenaTechnician
Nahia del TesoTechnician
Itziar FernándezDomínguezPhD Student
4. Vergara-Irigaray N, Chávarri-Martínez A, Rodríguez-Cuesta J, Miller
JF, Cotter PA, Martínez de Tejada G. Evaluation of the role of the Bvg
intermediate phase in Bordetella pertussis during experimental
respiratory infection. Infection and Immunity 73(2):748-760 (2005).
5. Lorenzo-Pajuelo B, Villanueva JL, Rodríguez-Cuesta J, Vergara-
Irigaray N, Bernabeu-Wittel M, Garcia-Curiel A, Martínez de Tejada G.
Cavitary pneumonia in an AIDS patient caused by an unusual
Bordetella bronchiseptica variant producing reduced amounts of
pertactin and other major antigens. Journal of Clinical Microbiology
40(9):3146-3154 (2002).
Lab Members
BIOSAFETY &RADIOACTIVEPROTECTION
Beatriz González CallejasBiosafety & RadioprotectionOfficer
This service is in charge of the proper operation of CIC bioGUNE´sRadioactive Facility including all activities carried out by theoperators and users, according to the rules provided by theOperation Authorization, the Protection Radiology Manual, theEmergency Plan and any other officially approved documentsobliging the users to observe such rules. As regards its biosafetyrole, the main duty of the service is to establish safe workingconditions by promoting good laboratory practices.
• Foreseeing needs of the center and fulfilling them.
• Supporting the strategic and corporate plan of the center.
Staff
Staff attachedto external projects
INFORMATICS
The service is responsible for providing scientific
and administrative computing, networking,
audiovisual and media services along with support
for centrally managed servers and applications.
High Performance Computing system has been implemented in
CIC bioGUNE to provide a huge boost in the computing capacity
available to researchers at the center. This accelerates projects
which already use HPC as a major tool and, in addition, will expand
the scope of researchers who are currently constrained to desktop
computing resources.
INFORMATICS SERVICE MAIN OBJECTIVES ARE:
• Offering a reliable and efficient service.
• Getting continuous improvement of services through
innovation and collaboration.
Gabriel CarasaInformatics Officer
Álvaro SáezGarcíaTechnician
Mónica Vega *Technician
Albano MartínezAlmeida *Technician
Itxaso UgarteTechnician
Maite GutiérrezCalzadaTechnician
Cristian PabloMankocTechnician
David ÁlvarezPeñarandaTechnician
Ewa Gubb *WebMaster
* External
The main task of this service is the development
and implementation of a preventive, predictive and
corrective maintenance in CIC bioGUNE.
Development of a predictive maintenance/external maintenance.
MAINTENANCE
José AntonioOvejeroTechnician
Sergio ÁlvarezRubioTechnician
Carles ChalauxMaintenance Officer
Staff
ADMINISTRATION& DIRECTOR’SOFFICE
The Administration Department at CIC bioGUNE is
responsible for the centre’s management and
administration functions and services, and reports
to the General Director and to the Board.
The Administration Department deals with all aspects of
governance of the centre, planning, organizing, coordinating and
maintaining supervision over the day-to-day administrative and
financial matters:
1. It manages purchases, budgeting control, administration of
grants and accounting for grants submission, and financial
forecasts to assist the General Director in the conduct of any
activity.
2. Administers personnel policies and functions related to human
resources, including recruitment, training and career
development.
3. Directs functions and coordinates activities of research-
supporting services.
4. Provides support for the exploitation of results and technology
transfer activities derived from research.
5. Coordinates the legal services and the development of the
adequate framework for all activities within the centre.
ADMINISTRATION& DIRECTOR’SOFFICE
The Administration Department works under the guides of
accountability, establishing criteria to measure the performance of
management and responding to the board from which they derive
their authority, and of transparency, which includes both the availability
of information and clarity about government rules, regulations, and
decisions.
CIC bioGUNE is commited to excellence at management levels placing
strong emphasis on enhancing the quality of professional administration
as part of our quest to achieve the best job performance.
Alfonso EgañaChief Financial Officer (CFO)
Mada RodríguezQuintanaHead ofAdministration
Bárbara MatoTechnician
LoliMontanosTechnician
José ManuelAparicioAccountingOfficer
Staff
Ana BarreiraTechnician
Alicia GonzálezGarcíaAssistant toGeneral Director
PROTEÍNAS DE FUSIÓN DE P53 SIN ACTIVIDAD DE TRANSCRIPCIÓN Y SUS APLICACIONES
METHOD FOR THE DIAGNOSIS OF NASH BASED ON METABOLIC PROFILES
UBIQUITIN BINDING POLYPETIDES 5’-METHYLTHIOADENOSINE (MTA) AS A MARKER OF LIVER INJURY
PROTEOMIC FINGERPRINT FOR THE DIAGNOSIS OF NON-ALCOHOLIC STEATOHEPATITIS (NASH) AND/OR STEATOSIS
SP1 AS A MARKER IN DIAGNOSIS AND PROGNOSIS OF NON-ALCOHOLIC STEATOHEPATITIS (NASH) AND TARGET IN DRUG SCREENING FOR NASH
PATENTS
0401
02 05
03 06
Centre: Centro de Investigación Cooperativa en Biociencias · CIC bioGUNE - OWL GenomicsDate: August 2008
Patent no.: EP08380249.6
Patented in: SPAIN/EUROPE
Exploitation: OWL Genomics
Centre: Centro de Investigación Cooperativaen Biociencias · CIC bioGUNEDate: June 2006
Patent no.: P200601537.0
Patented in: SPAIN
Exploitation: CIC bioGUNE · CI Príncipe Felipe
Centre: Centro de Investigación Cooperativa en Biociencias · CIC bioGUNEDate: February 2008 (EPO), February 2009 (USPTO)
Patent no.: EP08380059.9, US 12/389.660
Patented in: EUROPE/USA
Exploitation: Life Sensors
Centre: Centro de Investigación Cooperativa en Biociencias · CIC bioGUNE- University of VanderbiltDate: December 2006
Patent no.: US 11/963.691
Patented in: USA
Exploitation: OWL Genomics
Centre: Centro de Investigación Cooperativa en Biociencias · CIC bioGUNE - OWL GenomicsDate: July 2008
Patent no.: EP08380196.9
Patented in: SPAIN/EUROPEExploitation: OWL Genomics
Centre: Centro de Investigación Cooperativa en Biociencias · CIC bioGUNEDate: March 2005Patent no.: EP05075602.2/EP05077320.9/11/370068
Patented in: SPAIN/EUROPE/USA
Exploitation: OWL Genomics
DIAGNOSTIC AND PROGNOSTICMETHODS ON NON-ALCOHOLIC STEATOHEPATITIS(NASH)
Centre: Centro de Investigación Cooperativa en Biociencias · CIC bioGUNEDate: July 2004Patent no.: EP05780314.0/11/572.562
Patented in: EUROPE/USA
Exploitation: OWL Genomics
07
FUNDING
EUROPEAN UNION
BASQUE ADMINISTRATION
OTHER INSTITUTIONS
STATE GOVERNMENT
Postdoctoral ResearchersMINISTRY OF SCIENCE AND INNOVATIONNational Plan for Scientific Research, Development and Technological InnovationNational Program for Recruitment and Placement of Research Human Resources• Ramón y Cajal Subprogram Valerie Lang Juan Falcón Naiara Beraza
Xabier Aguirrezabala • Juan de la Cierva Subprogram Ashwin Woodhoo• University of Sassari Marcella Sini
National Plan for Scientific Research, Development and Technological InnovationResearch Activity and Complementary Actions Program• CONSOLIDER-INGENIO 2010 Research Activity Subprogram Mónika González López• Non-guided Basic Research Projects Subprogram Gorka Lasso
PROSTATE CANCER RESEARCH FOUNDATION Víctor Manuel Campa
NETWORK CENTRE FOR BIOMEDICAL RESEARCH IN LIVER AND GASTROINTESTINAL DISEASES. CIBERehd Marta Varela Félix Royo Fabienne Aillet
Platform SpecialistFOUNDATION FOR DEVELOPMENT OF RESEARCH IN GENOMICS AND PROTEOMICSSpanish National Institute Of Proteomics - PROTEORED Eva Rodríguez Suárez Ibon Iloro
AIDS TO RECRUITMENT FROM OTHER PUBLIC AND PRIVATE INSTITUTIONSPrincipal InvestigatorsMINISTRY OF SCIENCE AND INNOVATIONNational Plan for Scientific Research, Development and Technological InnovationNational Program for Recruitment and Placement of Research Human Resources• Ramón y Cajal Subprogram Manuel Rodríguez Medina James D Sutherland Aitor Hierro
IKERBASQUE FOUNDATIONFramework Agreement to Collaborate in the Promotion and Development of Research Nicola Abrescia Francisco Blanco Joaquín Castilla Ugo Mayor
BIZKAIA REGIONAL COUNCILAssociation for Mobility Supporting of Qualified People in Knowledge and innovation, Bizkaia:XEDE• GIZA:XEDE Program Mikel Valle Edurne Berra Lucy Malinina
Platform ManagersBIZKAIA REGIONAL COUNCILAssociation for Mobility Supporting of Qualified People in Knowledge and Innovation, Bizkaia:XEDE• GIZA:XEDE Program Tammo Diercks
TechniciansMINISTRY OF SCIENCE AND INNOVATIONNational Plan for Scientific Research, Development and Technological InnovationNational Program for Recruitment and Placement of Research Human Resources• Peer Technical Assistance (PTA) Subprogram Esperanza González Jiménez
Research Activity and Complementary Actions Program• Non-guided Basic Research Projects Subprogram Sara Pozo• CONSOLIDER-INGENIO 2010 Research Activity Subprogram Roland Hjerpe
NETWORK CENTRE FOR BIOMEDICAL RESEARCH IN LIVER AND GASTROINTESTINAL DISEASES. CIBERehd Aitziber González Lahera
PhD StudentsMINISTRY OF SCIENCE AND INNOVATIONNational Plan for Scientific Research, Developmentand Technological InnovationNational Program for Recruitment and Placement of Research Human Resources• Research Staff Training (FPI) Subprogram Valentine Comaills Rocío Jiménez Alonso Analía Elena Núñez O'Mara Leire Herboso Juan Luis García Rodríguez• Academic Staff Training (FPU) Subprogram Nuria Martínez López David Castaño
Research Activity and Complementary Actions Program• Non-guided Basic Research Projects Subprogram Elizaveta Katorcha
Carlos III Health Institute• Health Research Predoctoral Trainee Grants (PFIS) David Fernández Ramos• Biomedical and Health Sciences Research Promotion Program Javier Conde
BASQUE GOVERNMENT - EDUCATION, UNIVERSITIES AND RESEARCH DEPT.Program for Training and Improvement of the Research Staff• AE Modality: PhD Trainee Grants for staff researchers at R&D centres in Spain Guillermo Abascal Oihana Iriondo
SCIENCE AND TECHNOLOGY FOUNDATION Bruno Simões
LA CAIXA FOUNDATIONBiomedical Research Agreement Itziar Frades
BARCELONA SCIENCE PARK Xavier Tadeo
TECHNOLOGY CENTERS
PUBLIC ADMINISTRATION
COMPANIES
GENERAL ASSEMBLY
Parque Tecnológico de Bizkaia, Edificio 801A · 48160 DERIO · www.cicbiogune.es