CENTRO DE INVESTIGACION DEL CANCER

  • Laboratorio 1

Dr. Eugenio Santos

RAS GENE PRODUCTS IN PROLIFERATION AND DIFFERENTIATION SIGNALING PATHWAYS


Biography

Dr. Santos received his Ph.D. from the Department of Microbiology, University of Salamanca, in 1978. He carried out postdoctoral training at the Roche Institute of Molecular Biology (Nutley, NJ) (79-81) and the Laboratory of Cellular and Molecular Biology of the National Cancer Institute (NIH, Bethesda, MD) (81-84), where he later remained as a Principal Investigator until 2000, when he rejoined the University of Salamanca as Full Professor of Microbiology and Director of the Cancer Research Institute (USAL-CSIC).

Dr Santos’s scientific career has evolved closely in step with the field of molecular oncology. As a young postdoc at NCI in the early 1980s he cloned and characterized the first human oncogene (H-ras, from T24 bladder carcinoma cells). Following those seminal contributions that inaugurated the field of human oncogenes, his research has always focused on analysing the structure, function and regulation of the Ras family of genes and proteins. In the 1980s Santos completed the pioneering work of isolating the H-ras oncogene and demonstrating its oncogenic activation by point mutation, by demonstrating, for the first time in humans, the presence of an activated K-ras oncogene in the tumoural tissue – and its absence in the normal tissue – of the same patient. In the 1990s Dr Santos’s laboratory used Ras-dependent proliferation or differentiation models, such as Xenopus oocytes or 3T3L1 pre-adipocytes, to achieve further progress in understanding the structure and function of Ras proteins and their involvement in signal transduction pathways that control cell proliferation and differentiation in eukaryotes. Finally, from 2000 onwards, Santos’s research has demonstrated the functional specificity of the canonical members of the Ras family (H-ras, N-ras and K-ras) and their specific cellular activators (GEF, guanine nucleotide exchange factors) of the GRF and SOS families, using an experimental approach that involves the genomic and proteomic characterization of knockout mouse strains for several Ras and GEF genes.

Dr Santos is Spain’s national coordinator of the Spanish Cooperative Cancer Research Network (RTICC, sponsored by the Carlos III Health Institute). He sits on several editorial and scientific advisory boards, and has supervised more than fifty postdoctoral and postgraduate researchers throughout his scientific career. Santos is the recipient of several scientific awards, including the Severo Ochoa Award for Biomedical Research (1996) and the Echevarne Oncology Award (2010). He is a member of the Royal Academy of Medicine (RAMSA, Salamanca, Spain, 2003) and of the European Academy of Cancer Sciences (EACS, Brussels, 2011).

Dr. Eugenio  Santos
Contact

Dr. Eugenio Santos
Director, Centro de Investigación del Cancer.
Professor, Department of Microbiology and Genetics
University of Salamanca
Lab Nº1

923 294 720 (Ext. 4773)
923 294 743
cicancer(arroba)usal(.)es

Centro de Investigación del Cáncer (Universidad de Salamanca-CSIC)
Campus Universitario Miguel de Unamuno s/n
37007 Salamanca
SPAIN

Areas of Research

Since his isolation and characterization of the first human oncogene ( H-ras), Dr Santos´ scientific career has evolved in close temporal sync with the development of Molecular Oncology. Research in his group has always focused on the study of the structure, function and regulation of Ras family members. Current research is centered on the mechanisms regulating activation of Ras proteins by their specific upstream GEF regulators in physiological and pathological processes such as cancer. The experimental approach currently used in his lab involves molecular, cellular, and genomic/proteomic analyses of knockout mice strains defective in individual ras (H-ras, N-ras, K-ras) or GEF (RasGrf1, RasGrf2, Sos1, Sos2 ) genes, or combinations thereof, that were generated in his laboratory. Dr Santos´group is uniquely positioned to carry out this line of research based on the wide collection of Ras and GEF knockout strains generated in his lab during the last few years.

 The general aims of this research include (i) determining the specificity -or redundancy- of the functional participation of different Ras and GEF isoforms in various signal transduction pathways and (ii) ascertaining the cellular and molecular mechanisms controlling those processes in physiological or pathological contexts.

Accordingly, the following are specific interests and areas of experimental work in this group:

                -Identification of transcriptional patterns dependent on the expression of each individual Ras and GEF gene

                - Ascertaining the functional specificity or redundancy of the different members of the ras gene family (H-ras, N-ras, K-ras) and their regulators by nucleotide exchange (GEF family members Sos1, Sos2, Grf1 and Grf2).

                - Understanding the molecular mechanisms involved in the participation of these Ras and GEF molecules in physiological and pathological processes such as cancer in mammalian cells.

                - Linking structural and functional alterations of Ras and GEFs to specific clinical pathologies, in particular cancer

 The bulk of experimental evidence generated so far supports the working hypothesis of functional specificity for the different Ras and GEF isoforms analyzed:

                Regarding the functional specificity of the members of the Ras family (Genes Cancer 2011; Sci Signal 2014), recent work from this laboratory demonstrated that different Ras isoforms play distinct cellular roles, with a critical functional involvement of N-Ras in immune modulation/host defense and apoptotic responses (Oncogene 2007; Genome Biology 2009; Blood 2011; J Exp Med 2013), and K-Ras in progression through the G1/S phase of the cycle (EMBO J 2010; PLoS One 2010; BMC Genomics 2013). Collaborative studies also showed differential involvement of H-Ras and K-Ras in downstream signaling or the specific contribution of H-Ras to renal physiology and control of peripheral vascular pressure (Cell Signal 2009; World J Urol 2009; Kidney Int 2010; Hypertension 2010; Am J Physiol Cell Physiol 2012; BBA-MCR 2013).

                The study of our single or double RasGrf1/ RasGrf2 knockout mice has also documented their differential functionality (BBA Rev Cancer 2011) demonstrating that RasgGrf1 plays specific roles in control of pancreatic beta cells (Embo J 2003; BMC Genomics 2014) and neurosensory processes including visual photoreception (Neuroscience 2007; J. Neurochem 2009) and that RasGrf2 cooperates with Vav proteins in T cell signaling and lymphomagenesis (Mol Cell Biol 2007; PLoS One 2009). Recent work participating in international consortiums performing GWAS (genome wide association study meta-analysis of directly genotyped or imputed human SNPs) studies supports a role of RasGrf1 in predisposition to myopia and refractive errors of vision (Nat. Genetics 2010) and of RasGrf2 in predisposition to addictive substance (alcohol) abuse (PNAS 2011, 2012; Psychopharmacology 2014).

                Separate work has also analyzed the specific functionality of members of the mammalian Sos family of RasGEF activators. Analysis of constitutive KO mice for these two loci showed previously that Sos 1 is essential for embryonic development (EMBO J 2000) whereas Sos2 is perfectly dispensable in adult mice and its absence does not produce any obvious phenotype (Mol Cell Biol 2000). However, recent work using a tamoxifen-inducible Sos1-null mouse strain showed that Sos1/2 double-knockout (DKO) animals die precipitously whereas individual Sos1 and Sos2 adult knockout (KO) mice are perfectly viable, thus demonstrating functional redundancy between Sos1 and Sos2 for homeostasis and survival of the full organism and for development and maturation of T and B lymphocytes (Mol Cell Biol 2013).

Projects
  • INSTITUTO DE SALUD CARLOS III (2016-)

    l objetivo principal de este proyecto es analizar la función y especificidad de las proteínas Ras y sus activadores GEF, así como la búsqueda de inhibidores de la acción de dichos GEF sobre las GTPasas Ras. El proyecto se basa en 1) el empleo de ratones modificados genéticamente, así cómo cultivos celulares procedentes de los mismos para los estudios de especificidad y 2) en el empleo de un método basado en la emisión de fluorescencia para analizar la acción GEF en el screening de inhibidores. Los sujetos de este estudio son: ratones KO para H-Ras, N-Ras, K-Ras, así como las distintas combinaciones de dichos genotipos; ratones deficientes en Sos1, Sos2 y en ambos GEF y animales carentes de GRF1, GRF2 y de ambas proteínas. Los resultados obtenidos muestran un papel para las proteínas H-Ras y N-Ras en maduración pulmonar y diferenciación de neumocitos en las últimas etapas de desarrollo embrionario, que no puede ser reemplazada por la acción de K-Ras. Así mismo hemos comprobado el papel específico de Sos1 en desarrollo de tumores epiteliales, migración y adhesión, así cómo el distinto papel que tienen Sos1 y Sos2 en desarrollo linfocitario. Además de estos datos, hemos visto que Grf2 tiene un papel específico en neurogénesis adulta y desarrollo retiniano, mientras que Grf1 lo tiene en desarrollo de células beta del páncreas y del cristalino. Todos estos datos apuntan a que tanto las proteínas Ras como sus activadores de las familias Sos y Grf, tienen un papel específico en procesos fisiológicos concretos, pese a tener también un papel redundante para muchos otros. ESTE PROYECTO ESTÁ COFINANCIADO POR EL FONDO EUROPEO DE DESARROLLO REGIONAL (FEDER). “Una manera de hacer Europa”

  • Junta de Castilla y León (2014-2015)

    Activadores Ras-GEF de las familias Sos y Grf como marcadores y dianas en procesos de desarrollo normal y tumoral

  • Instituto de Salud Carlos III (2014-2016)

    Activación de oncoproteínas Ras por GEFs de las familias Sos y Grf y su implicación en procesos fisiológicos y tumorales. Validación como biomarcadores y/o dianas terapéuticas

  • Ministerio de Economía y Competitividad/Instituto de Salud Carlos III . (2013-2016)

    Red Temática de Investigación Cooperativa en Cáncer (RD12/0036/0001)

  • Fundación Solórzano (2013-2013)

    Papel de las proteínas SOS en el desarrollo y maduración de los linfocitos B y T

  • Fundación Lucha Contra La Ceguera (FUNDALUCE) (2013-2013)

    Los ratones KNOCKOUT para RASGRF1 y RASGRF2 como modelos de degeneración retiniana

  • Junta de Castilla y León (2011-2000)

    Convenio de Subvención directa Consejería Educacion a la Fundación de Investigación del Cáncer.

  • Insituto de Salud Carlos III (2010-2013)

    Mecanismos de especificidad funcional de oncoproteinas RAS y sus activadores celulares específicos GEF en procesos fisiológicos y patológicos

  • Junta de Castilla y Leon (2008-2010)

    Especificidad funcional de proteinas ras y sus activadores gef en procesos fisiológicos y patológicos

  • Junta de Castilla y Leon (2008-2010)

    Especificidad funcional de proteinas ras y sus activadores gef en procesos fisiológicos y patológicos

  • Junta de Castilla y León (2008-2010)

    Estudios de especifidad funcional de oncoproteinas ras y sus activadores celulares

  • Instituto de Salud Carlos III (2007-2009)

    MECANISMOS DE ACTIVACIÓN DE ONCOPROTEINAS RAS: ANALISIS DE ESPECIFICIDAD FUNCIONAL DE DIANAS RAS Y SUS ACTIVADORES GEF EN PROCESOS FISIOLOGICOS Y PATOLOGICOS

  • Instituto de Salud Carlos III (2007-2007)

    Instituto de Salud Carlos III.

  • UNIVERSIDAD DE SALAMANCA (2006-0000)

    CURSOS DE DOCTORADO

  • JUNTA DE CASTILLA Y LEON (2005-2007)

    dAnálisis funcional de las familias SOS y GRF de activadores de proteínas RAS.

  • MINISTERIO DE CINECIA Y TECNOLOGÍA (2004-2007)

    ANALISIS FUNCIONAL DE PROTEÍNAS RAS EN RATONES MOSIFICADOS GENETICAMENTE

  • Ministerio de Ciencia y Tecnologia (2003-2006)

    Especificidad funcional de isoformas de la familia RAS

  • JUNTA DE CASTILLA Y LEON (2002-2004)

    Análisis de la función in vivo de protínas RAS y su activación por intercambiadores de nucleotidos GEFS

  • Instituto de Salud Carlos III (2002-2005)

    Implicación de proteinas RAS y sus activadores GEF en procesos fisiológicos y patológicos: estudio genómico usando modelos animales KNOCKOUT.

  • (-)

    Convenio de Subvención directa Consejería Educacion a la Fundación de Investigación del Cáncer.

Junta de Castilla y León Ministerio de economía y competitividad Fondo europeo de desarrollo regional
Publications

(*) Means equal contribution as senior authors.



2020
2019
2018
2017
2016

A translational systems biology approach in both animals and humans identifies a functionally related module of accumbal genes involved in the regulat

Stacey D, Lourdusamy A, Ruggeri B, Maroteaux M, Jia T, Cattrell A, Nymberg C, Banaschewski T, Bhattacharyya S, Band H, Barker G, Bokde A, Büchel C, Carvalho F, Conrod P, Desrivières S, Easton A, Fauth-Buehler M, Fernandez-Medarde A, Flor H, Frouin V, Gallinat J, Garavanh H, Heinz A, Ittermann B, Lathrop M, Lawrence C, Loth E, Mann K, Martinot JL, Nees F, Paus T, Pausova Z, Rietschel M, Rotter A, Santos E, Smolka M, Sommer W, Mameli M, Spanagel R, Girault JA, Mueller C, Schumann G, , 
J Psychiatry Neurosci; 2016; 41(3); 192-202; 26679926


2014
2013
2012

RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release.

Stacey D, Bilbao A, Maroteaux M, Jia T, Easton AC, Longueville S, Nymberg C, Banaschewski T, Barker GJ, Büchel C, Carvalho F, Conrod PJ, Desrivières S, Fauth-Bühler M, Fernandez-Medarde A, Flor H, Gallinat J, Garavan H, Bokde AL, Heinz A, Ittermann B, Lathrop M, Lawrence C, Loth E, Lourdusamy A, Mann KF, Martinot JL, Nees F, Palkovits M, Paus T, Pausova Z, Rietschel M, Ruggeri B, Santos E, Smolka MN, Staehlin O, Jarvelin MR, Elliott P, Sommer WH, Mameli M, Müller CP, Spanagel R, Girault JA, Schumann G, , 
Proc. Natl. Acad. Sci. U.; 2012; 109(51); 21128-33; 23223532


2011

Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumptio

Schumann G, Coin LJ, Lourdusamy A, Charoen P, Berger KH, Stacey D, Desrivières S, Aliev FA, Khan AA, Amin N, Aulchenko YS, Bakalkin G, Bakker SJ, Balkau B, Beulens JW, Bilbao A, de Boer RA, Beury D, Bots ML, Breetvelt EJ, Cauchi S, Cavalcanti-Proença C, Chambers JC, Clarke TK, Dahmen N, de Geus EJ, Dick D, Ducci F, Easton A, Edenberg HJ, Esko T, Esk T, Fernandez-Medarde A, Foroud T, Freimer NB, Girault JA, Grobbee DE, Guarrera S, Gudbjartsson DF, Hartikainen AL, Heath AC, Hesselbrock V, Hofman A, Hottenga JJ, Isohanni MK, Kaprio J, Khaw KT, Kuehnel B, Laitinen J, Lobbens S, Luan J, Mangino M, Maroteaux M, Matullo G, McCarthy MI, Mueller C, Navis G, Numans ME, Núñez A, Nyholt DR, Onland-Moret CN, Oostra BA, O'Reilly PF, Palkovits M, Penninx BW, Polidoro S, Pouta A, Prokopenko I, Ricceri F, Santos E, Smit JH, Soranzo N, Song K, Sovio U, Stumvoll M, Surakk I, Thorgeirsson TE, Thorsteinsdottir U, Troakes C, Tyrfingsson T, Tönjes A, Uiterwaal CS, Uitterlinden AG, van der Harst P, van der Schouw YT, Staehlin O, Vogelzangs N, Vollenweider P, Waeber G, Wareham NJ, Waterworth DM, Whitfield JB, Wichmann EH, Willemsen G, Witteman JC, Yuan X, Zhai G, Zhao JH, Zhang W, Martin NG, Metspalu A, Doering A, Scott J, Spector TD, Loos RJ, Boomsma DI, Mooser V, Peltonen L, Stefansson K, van Duijn CM, Vineis P, Sommer WH, Kooner JS, Spanagel R, Heberlein UA, Jarvelin MR, Elliott P, 
Proc. Natl. Acad. Sci. U.; 2011; 108(17); 7119-24; 21471458

RasGrf1 deficiency delays aging in mice.

Borrás C, Monleón D, López-Grueso R, Gambini J, Orlando L, Pallardó FV, Santos E, Viña J, Font de Mora J, 
Aging (Albany NY); 2011; 3(3); 262-76; 21422498


2010
2009
2008
2007
2006
2005
2004
-
Patents
  • Animal models and derived cells for use thereof in determination of useful compounds in the treatment of T-cell lymphomas
    García Bustelo Xosé Ramón Ruiz Macías Sergio Santos De Dios Eugenio
    ES2341213 (A1) WO2010070170 (A1); 2008-12-15

  • Animal models and derived cells for use thereof in determination of useful compounds in the treatment of T-cell lymphomas
    García Bustelo Xosé Ramón / Ruiz Macías Sergio / Santos De Dios Eugenio
    ES2341213 (A1) WO2010070170 (A1); 2008-12-15

Group
  • Dr. Eugenio  Santos Dr. Eugenio Santos

    Dr. Eugenio Santos

    RAS GENE PRODUCTS IN PROLIFERATION AND DIFFERENTIATION SIGNALING PATHWAYS

    Telf.: +34 923 294 801

    Fax:

    Email: esantos@usal.es


    Contact

    Dr. Eugenio Santos de Dios
    Investigador Principal y director del Centro de Investigación del Cáncer
    Laboratorio Nº 1.

    Catedrático, Departamento de Microbiología y Genética de la Universidad de Salamanca.

    923 294 720 (Ext. 4773)
    923 294 743
    cicancer(arroba)usal(.)es

    Centro de Investigación del Cáncer (Universidad de Salamanca-CSIC)
    Campus Universitario Miguel de Unamuno s/n
    37007 Salamanca
    SPAIN


    Biography

    Dr. Santos received his Ph.D. from the Department of Microbiology, University of Salamanca, in 1978. He carried out postdoctoral training at the Roche Institute of Molecular Biology (Nutley, NJ) (79-81) and the Laboratory of Cellular and Molecular Biology of the National Cancer Institute (NIH, Bethesda, MD) (81-84), where he later remained as a Principal Investigator until 2000, when he rejoined the University of Salamanca as Full Professor of Microbiology and Director of the Cancer Research Institute (USAL-CSIC).

    Dr Santos’s scientific career has evolved closely in step with the field of molecular oncology. As a young postdoc at NCI in the early 1980s he cloned and characterized the first human oncogene (H-ras, from T24 bladder carcinoma cells). Following those seminal contributions that inaugurated the field of human oncogenes, his research has always focused on analysing the structure, function and regulation of the Ras family of genes and proteins. In the 1980s Santos completed the pioneering work of isolating the H-ras oncogene and demonstrating its oncogenic activation by point mutation, by demonstrating, for the first time in humans, the presence of an activated K-ras oncogene in the tumoural tissue – and its absence in the normal tissue – of the same patient. In the 1990s Dr Santos’s laboratory used Ras-dependent proliferation or differentiation models, such as Xenopus oocytes or 3T3L1 pre-adipocytes, to achieve further progress in understanding the structure and function of Ras proteins and their involvement in signal transduction pathways that control cell proliferation and differentiation in eukaryotes. Finally, from 2000 onwards, Santos’s research has demonstrated the functional specificity of the canonical members of the Ras family (H-ras, N-ras and K-ras) and their specific cellular activators (GEF, guanine nucleotide exchange factors) of the GRF and SOS families, using an experimental approach that involves the genomic and proteomic characterization of knockout mouse strains for several Ras and GEF genes.

    Dr Santos is Spain’s national coordinator of the Spanish Cooperative Cancer Research Network (RTICC, sponsored by the Carlos III Health Institute). He sits on several editorial and scientific advisory boards, and has supervised more than fifty postdoctoral and postgraduate researchers throughout his scientific career. Santos is the recipient of several scientific awards, including the Severo Ochoa Award for Biomedical Research (1996) and the Echevarne Oncology Award (2010). He is a member of the Royal Academy of Medicine (RAMSA, Salamanca, Spain, 2003) and of the European Academy of Cancer Sciences (EACS, Brussels, 2011).

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  • Alberto  Fernández Medarde Alberto Fernández Medarde

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    Role for Ras Guanine Nucleotide Exchange Factors RasGrf1 and RasGrf2 in Central Nervous System

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    Role of Ras GEFs RasGrf1 and RasGrf2 in the Central Nervous System. Characterization of the proteins involved in physiological processes regulated by these GEFs: photoreception and memory generation.

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  • Rocío Fuentes Mateos Rocío Fuentes Mateos

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    Characterization of the phenotypical alterations in H-Ras & N-Ras double KO mice

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