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Timothy Thomson: Cell signalling, ubiquitin and cancer

Lab Presentation

  • Mechanisms of neoplasia and malignant progression using cellular and animal models.
  • Role of the ubiquitin-proteasome system in the regulation of cell cycle checkpoints and the recognition and repair of DNA damage.
  • Design and development of new drugs targeted at regulators of the ubiquitin-proteasome system of interest in cancer and other pathologies.

Research Lines

Study of mechanisms of neoplasia and malignant progression
Discovery of new genes and pathways relevant in malignancy and in the development of metastasis, useful as markers useful in diagnosis and prognosis and the identification of novel pathways for the development of effective new therapeutic schemes to tackle the problem of metastatic spread of cancer.
Study of the role of the ubiquitin-proteasome system in relevant cellular processes
Role of non-canonical ubiquitylation (through K63 of ubiquitin), mediated by the ubiquitin-conjugating enzyme Ubc13-Uev, and role of the ubiquitin ligase RNF8 in checkpoint control and in the establishment of the DNA damage response.
Drug design and development
Discovery of novel antagonists of protein-protein interaction with relevance in the regulation of the ubiquitin-proteasome system. After in vitro and in vivo validation in cancer models, our aim is to take compounds with effective anti-tumor activity to preclinical and, eventuall, clinical phases.
Timothy Thomson Okatsu
  • Dr. Timothy M. Thomson
  • IBMB-CSIC
  • C/ Baldiri Reixac, 15-21
  • 08028 Barcelona, Spain
  • Phone: +34 93 402 0199
  • E-mail: titbmc@ibmb.csic.es

Principal Investigator



Past students

  • Diaz VM, Planaguma J, Thomson TM, Reventos J, Paciucci R. Tissue plasminogen activator is required for the growth, invasion, and angiogenesis of pancreatic tumor cells. Gastroenterology vol. 122, 806-819 (2003).
     
  • Diaz VM, Hurtado M; Thomson TM, Reventos J, Paciucci R. Specific interaction of tissue-type plasminogen activator (t-PA) with annexin II on the membrane of pancreatic cancer cells activates plasminogen and promotes invasion in vitro. Gut vol. 53,  993 – 1000 (2004).
     
  • Diaz VM, Hurtado M, Kort EJ, Resnati M, Blasi F, Thomson T, Paciucci R. Requirement of the enzymatic and signaling activities of plasmin for phorbol-ester-induced scattering of colon cancer cells. Experimental Cell Research vol. 312, 2203 – 2213 (2006).
     
  • Ferrer B, Bermudo R, Thomson T, Nayach I, Soler M, Sanchez M, Castillo M, Calvo J, Campo E, Fernandez PL. Paraffin-embedded cell line microarray (PECLIMA): Development and validation of a high-throughput method for antigen profiling of cell lines. Pathobiology vol. 72, 225  -  232 (2005).
     
  • Lozano JJ, Soler M, Bermudo R, Abia D, Fernandez PL, Thomson TM, Ortiz AR. Dual activation of pathways regulated by steroid receptors and peptide growth factors in primary prostate cancer revealed by Factor Analysis of microarray data. BMC Genomics vol. 6, 1  -  18 (2005).
     
  • Plans V, Scheper J, Soler M, Loukili N, Okano Y, Thomson TM. The RING finger protein RNF8 recruits UBC13 for lysine 63-based self polyubiquitylation. J Cell Biochem vol. 97, 572 – 582 (2006).
     
  • Kolas NK, Chapman JR, Nakada S, Ylanko J, Chahwan R, Sweeney FD, Panier S, Mendez M, Wildenhain J, Thomson TM, Pelletier L, Jackson SP, Durocher D. Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science vol. 318, 1637 – 1640 (2007).
     
  • Plans V, Guerra-Rebollo M, Thomson TM (2008). Regulation of mitotic exit by the RNF8 ubiquitin ligase. Oncogene vol. 27, 1355 - 1365 (2008).
     
  • Scheper J, Oliva B, Villà-Freixa J, Thomson TM. Analysis of electrostatic contributions to the selectivity of interactions between RING-finger domains and ubiquitin-conjugating enzymes. Proteins vol. 74, 92 - 103 (2008).
     
  • Bermudo R, Abia D, Ferrer B, Nayach I, Benguria A, Zaballos A, del Rey J, Miró R, Campo E, Martínez-A C, Ortiz AR, Fernández PL, Thomson TM. Co-regulation analysis of closely linked genes identifies a highly recurrent gain on chromosome 17q25.3 in prostate cancer. BMC Cancer vol. 8, 315 (2008).
     
  • Soler M, Mancini F, Meca-Cortés O, Sánchez-Cid L, Rubio N, López-Fernández S, Lozano JJ, Blanco J, Fernández PL, Thomson TM. HER3 is required for the maintenance of neuregulin-dependent and –independent attributes of malignant progression in prostate cancer. Int J Cancer vol. 125, 2565-2575 (2009).
     
  • Crosas B, Farràs R, Marfany G, Rodríguez MS, Thomson TM. Searching for the boundaries: unlimited expansion of ubiquitin and ubiquitin-like signals in multiple cellular functions. Biochem Soc Trans vol. 38 (Pt 1), 1-5 (2010).
     
  • Thomson TM, Guerra-Rebollo M. Ubiquitin and SUMO signaling in DNA Repair. Biochem Soc Trans vol. 38 (Pt 1), 116-131 (2010).
     
  • Isasa M, Katz E, Kim W, Yugo V, González S, Kirkpatrick DS, Thomson TM, Finley D, Gygi SP, Crosas B. Monoubiquitination of Rpn10 regulates substrate recruitment to the proteasome. Mol Cell vol. 38(5), 733-45 (2010).
     
  • Gómez V, Sesé M, Santamaría A, Martínez JD, Castellanos E, Soler M, Thomson TM, Paciucci R. Regulation of Aurora B kinase by the lipid raft protein Flotillin-1.J Biol Chem 285(27), 20683-90 (2010).
     
  • Scheper J, Guerra-Rebollo M, Moure A, Masip I, González-Ruiz D, Rubio N, Crosas B, Meca-Cortés O, Loukili N, Plans V, Morreale A, Blanco J, Ortiz AR, Messeguer A, Thomson TM. Protein-protein interaction antatonists as novel inhibitors of non-canonical polyubiquitylation. PLOS One vol. 5(6), e11403 (2010).
     
  • Bermudo R, Abia D, Benítez D, Carrió A, Vilella R, Ortiz AR, Thomson TM, Fernández PL. discovery of genomic alterations through coregulation analysis of closely linked genes: a frequent gain in 17q25.3 in prostate cancer. Ann NY Acad Sci vol. 210 (1), 17-24 (2010).
     
  • Korpal M, Ell BJ, Buffa FM, Ibrahim T, Blanco MA, Celià-Terrassa T, Mercatali L, Khan Z, Goodarzi H, Hua Y, Wei Y, Hu G, Garcia BA, Ragoussis J, Amadori D, Harris AL, Kang Y. Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat Med vol. 17(9), 1101-8 (2011).
     
  • Lok GT, Sy SM, Dong SS, Ching YP, Tsao SW, Thomson TM, Huen MS. Differential regulation of RNF8-mediated Lys48- and Lys63-based poly-ubiquitylation. Nucleic Acids Res vol. 40 (1), 196-205 (2011).
     
  • Bermudo R, Abia D, Mozos A, García E, Alcaraz A, Ortiz AR, Thomson TM, Fernández PL. Highly sensitive molecular diagnosis of prostate cancer using surplus material washed off from biopsy needles. Br J Cancer vol. 105 (10), 1600-7 (2011).
     
  • Celià-Terrassa T, Meca-Cortés O, Mateo F, Martínez de Paz A, Rubio N, Arnal-Estapé A, Ell BJ, Bermudo R, Díaz A, Guerra-Rebollo M, Lozano JJ, Estarás C, Ulloa C, Álvarez-Simón D, Milà J, Vilella R, Paciucci R, Martínez-Balbás M, García de Herreros A, Gomis RR, Kang Y, Blanco J, Fernández PL, Thomson TM. Epithelial-mesenchymal transition can suppress major attributes of epitelial tumor-initiating cells. J Clin Invest 122(5), 1849-1868 (2012).
     
  • Guerra-Rebollo M, Mateo F, Franke K, Huen MSY, Lopitz-Otsoa F, Rodríguez MS, Plans V, Thomson TM. Nucleolar exit of RNF8 and BRCA1 in response to DNA damage. Exp Cell Res 318(18), 2365-76 (2012).
     
  • Zhang S, Zhou Y, Sarkeshik A, Yates J, Thomson TM, Zhang Z, Lee EY, Lee MY. Identification of RNF8 as a ubiquitin ligase involved in targeting the p12 subunit of DNA polymerase δ for degradation in response to DNA damage. J Biol Chem 288(5), 2941-50 (2013).
     
  • Marqués M, Cánovas V, Sesé M, Valente F, Bermudo R, Torres I, Fernández Y, Abasolo I, Fernández PL, Contreras H, Castellón E, Celià-Terrassa T, Méndez R, Ramón y Cajal S, Thomson TM, Paciucci R. Regulation of protein translation and c-Jun expression by Prostate Tumor Overexpressed 1 (PTOV1). Oncogene (in press) (2013).
     
  • Camacho L, Meca-Cortes O, Abad JL, Garcia S, Rubio N, Diaz A, Celia-Terrassa T, Cingolani F, Bermudo R, Fernandez PL, Blanco J, Delgado A, Casas J, Fabrias G, Thomson TM. Acid ceramidase as a therapeutic target in metastatic prostate cancer. J Lipid Res (in press) (2013).
     
  • Mateo F, Fernández PL, Thomson TM. Stem cells in prostate cancer. Arch Esp Urol (in press) (2013).

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Nuevos métodos de cribaje combinado, experimental y virtual, para la identificación y desarrollo de pequeñas moléculas de interferencia específica de interacciones proteína-proteína y desacoplamiento de rutas de señalización

  • AGENCY: CSIC
  • PERIOD: 11/2005  - 10/2007
  • PI: Timothy M Thomson
     

Genes de malignidad en cáncer de próstata: validación de PTOV1 como diana terapéutica mediante administración in vivo de siRNA e identificación no sesgada de determinantes moleculares de metástasis

  • AGENCY: Programa Nacional de Biomedicina, MEC
  • PERIOD: 12/2005  - 12/2008
  • PI: Timothy M Thomson
     

New molecules in the diagnosis and therapy of prostate and breast cancers. Modulation of tumor growth by the chemokine CX3CL1 (Fractalkine)

  • AGENCY: Fundació La Marató de TV3
  • PERIOD: 12/2005  -  12/2008
  • PI: Timothy M Thomson
     

Nuevos marcadores de malignidad identificados mediante procedimientos de alto rendimiento. Desarrollo y demostración de nuevas plataformas para el diagnóstico molecular de cáncer de próstata

  • AGENCY: PROG. DE ESTIMULO A LA TRANS. DE RESULTADOS DE INVESTIGACION, MEC
  • PERIOD: 12/2006  -  12/2008
  • PI: Timothy M Thomson
     

Regulation of gene networks common to cancer stem cells and malignant progression

  • AGENCY: Spanish Ministry of Education and Science
  • PERIOD: 01/2009 - 12/2011
  • PI: Timothy M Thomson
     

Estudio fenotípico de células madre neoplásicas y de su transición epitelio-mesénquima en muestras exvivo derivadas de adenocarcinomas prostáticos humanos.

  • AGENCY: Spanish Ministry of Foreign Affairs (AECID)
  • PERIOD: 01/2009 - 12/2009
  • PI: Timothy M Thomson 
     

Desarrollo preclínico de nuevos compuestos antitumorales

  • AGENCY: Generalitat de Catalunya (CIDEM)
  • PERIOD: 06/2009 - 06/2010
  • PI: Timothy M. Thomson 
     

Grupo reconocido y financiado por la Generalitat de Catalunya "Cáncer, señalización y ubiquitinación"

  • AGENCY: Generalitat de Catalunya AGAUR SGR-DGR
  • PERIOD: 2009 - 2014
  • PI: Timothy M Thomson 

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