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The Role of P19 C-H-Ras Protein in Metastasis and Proliferative Pathways Roseli Marlen García Cruz

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The Role of P19 C-H-Ras Protein in Metastasis and Proliferative Pathways Roseli Marlen García Cruz The role of p19 C-H-Ras protein in metastasis and proliferative pathways Roseli Marlen García Cruz ADVERTIMENT. La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX (www.tdx.cat) i a través del Dipòsit Digital de la UB (diposit.ub.edu) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX ni al Dipòsit Digital de la UB. No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX o al Dipòsit Digital de la UB (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. En la utilització o cita de parts de la tesi és obligat indicar el nom de la persona autora. ADVERTENCIA. La consulta de esta tesis queda condicionada a la aceptación de las siguientes condiciones de uso: La difusión de esta tesis por medio del servicio TDR (www.tdx.cat) y a través del Repositorio Digital de la UB (diposit.ub.edu) ha sido autorizada por los titulares de los derechos de propiedad intelectual únicamente para usos privados enmarcados en actividades de investigación y docencia. No se autoriza su reproducción con finalidades de lucro ni su difusión y puesta a disposición desde un sitio ajeno al servicio TDR o al Repositorio Digital de la UB. No se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR o al Repositorio Digital de la UB (framing). Esta reserva de derechos afecta tanto al resumen de presentación de la tesis como a sus contenidos. En la utilización o cita de partes de la tesis es obligado indicar el nombre de la persona autora. WARNING. On having consulted this thesis you’re accepting the following use conditions: Spreading this thesis by the TDX (www.tdx.cat) service and by the UB Digital Repository (diposit.ub.edu) has been authorized by the titular of the intellectual property rights only for private uses placed in investigation and teaching activities. Reproduction with lucrative aims is not authorized nor its spreading and availability from a site foreign to the TDX service or to the UB Digital Repository. Introducing its content in a window or frame foreign to the TDX service or to the UB Digital Repository is not authorized (framing). Those rights affect to the presentation summary of the thesis as well as to its contents. In the using or citation of parts of the thesis it’s obliged to indicate the name of the author. ACKNOWLEGDMENTS The following thesis, while an individual work, benefited from the insights and direction of several people. First at all, my Thesis Chair, Dr. Montserrat Bach-Elias, for welcoming me into her group, and for her knowledgeable guidance and continuous education throughout these years. I also want to mention my gratitude to the Consejo Nacional de Ciencia y Tecnología (CONACYT) of Mexico for providing me financial support to pursue my doctoral studies at Universidat de Barcelona. CONACYT is a Mexican government agency and therefore the author is also grateful to the mexican people that make possible CONACYT’s mission. I am also very grateful to Dr. Sol-Church for accepting me as a student and for her wise criticism during my stay research training in Core Laboratory at Alfred I. Dupont Nemours Hospital for children in Wilmington, Delaware, USA. My warmest thanks also extended to my work mate and colleague Maria Camats for teaching me in my first training at the laboratory and generous encouragement for helping me in some experiments. I am particularly grateful for the technical assistance provided by Dr. Jaume Comas Riu, for his assistance in the cytometry analyses realized at Parc Cientific of Universitat de Barcelona. I would like to warmly show my gratitude for the extremely loving support provided by my dearest family and mexican and spanish friends, who, even from the distance, have always strongly approved my decisions and encouraged me to persevere, to my mother Lucía, my beloved husband Carlos Armando who encouraged me to written the last part of my thesis and to my brother José Luis and my sister Lizbeth; and in a special manner this thesis is dedicated to my grandmother’s memory Francisca, who lost her battle against cancer. I also ii want to thank for my best friends Luz del Carmen Camacho, Juan Carlos Flores, Ana Navarro, Sabine Schnell, Úrsula Flores, Araní Casillas and Hiram. Finally, my last and sincere debt of gratitude goes to my beloved friends in Wilmington, Delaware, USA, especially to Deborah Stanley, Ilsa Gómez, Brenda, and Suzanne Purfield who have made my life in the city of Wilmington incredibly enjoyable and unforgettable during my stay. FUNDS This project had financial support of “Eugenio Rodríguez Pascual” Foundation, Spain. Roseli Marlen’s PhD scholarship was granted by CONACYT-MEXICO (Consejo Nacional de Ciencia y Tecnología). iii TABLE OF CONTENTS Pages List of figures....................................................................................................... xi List of tables........................................................................................................ xii List of graphics.................................................................................................... xiv List of abbreviations............................................................................................ xvi Summary.............................................................................................................. xxiv I. INTRODUCTION.......................................................................................... 1 1.1 CANCER...................................................................................................... 1 1.1.2 Carcinogenesis............................................................................................ 1 1.1.3 Molecular basis of cancer phenotypes........................................................ 3 1.1.4 Cancer related genes................................................................................... 5 A) Oncogenes (OG)........................................................................................... 5 B) Tumour suppressor genes (TSG).................................................................. 6 C) Metastasis suppressor genes (MSG)............................................................. 7 1.1.5 Tumour microenvironment......................................................................... 9 1.1.5.1 Reactive oxygen species (ROS).............................................................. 9 1.2 RAS MAMMALIAN GENES FAMILY.................................................... 10 1.2.1 Localization of Ras proteins in the cell..................................................... 11 1.2.2 Ras signal transduction.............................................................................. 12 A) Ras/Raf/MAPK pathway............................................................................. 15 B) JNK/SAPK pathway..................................................................................... 15 C) PI3K/AKT pathway...................................................................................... 16 D) Ral GEF pathway......................................................................................... 17 1.2.3 Oncogenic activation of Ras....................................................................... 17 1.3 H-RAS ALTERNATIVE SPLICING........................................................ 21 1.3.1 Alternative splicing..................................................................................... 21 1.3.2 Alternative splicing of c-H-Ras gene renders two proteins: p21 and p19.. 22 1.3.3 p19 c-H-Ras protein.................................................................................... 24 1.3.3.1 Intracellular signalling pathways of p19 protein..................................... 25 A) RACK1 and pKC pathway.......................................................................... 25 B) MEK 1/2 pathway........................................................................................ 25 C) c-Jun pathway............................................................................................. 26 D) TSC pathway............................................................................................... 26 1.3.3.2 P19 induces an irreversible quiescence state in cell cycle...................... 26 1.3.3.3 The role of p19 c-H-Ras protein in cancer and metastasis processes.... 26 1.4 COSTELLO SYNDROME (CS)................................................................ 27 1.4.1 Definition and disease characteristics......................................................... 27 1.4.2 H-Ras mutations in Costello Syndrome..................................................... 28 1.4.3 Diagnosis/ testing....................................................................................... 29 1.4.4 Costello solid tumours................................................................................ 29 1.4.5 In vivo systems for studying Costello Syndrome....................................... 29 iv A) Mouse model ............................................................................................... 29 B) Zebrafish model ........................................................................................... 31 1.5 MIRNAs.......................................................................................................
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