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Papel Funcional De Los Miembros De La Familia Retinoblastoma (Prb, P107 Y P130) En Los Procesos De Proliferación, Diferenciación Y Cercinogénesis De Piel De Ratón

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Papel Funcional De Los Miembros De La Familia Retinoblastoma (Prb, P107 Y P130) En Los Procesos De Proliferación, Diferenciación Y Cercinogénesis De Piel De Ratón UNIVERSIDAD COMPLUTENSE DE MADRID FACULTAD DE CIENCIAS BIOLÓGICAS Departamento de Bioquímica y Biología Molecular PAPEL FUNCIONAL DE LOS MIEMBROS DE LAQ FAMILIA RETINOBLASTOMA (pRb, p107 y p130) EN LOS PROCESOS DE PROLIFERACIÓN, DIFERENCIACIÓN Y CERCINOGÉNESIS DE PIEL DE RATÓN MEMORIA PARA OPTAR AL GRADO DE DOCTOR PRESENTADA POR Sergio Ruíz Macías Bajo la dirección de Los doctores Jesús M. Paramio González José Luis Jorcano Madrid, 2004 ISBN: 84-669-2477-9 UNIVERSIDAD COMPLUTENSE DE MADRID FACULTAD DE CIENCIAS BIOLÓGICAS DEPARTAMENTO DE BIOQUÍMICA Y BIOLOGÍA MOLECULAR TESIS DOCTORAL PAPEL FUNCIONAL DE LOS MIEMBROS DE LA FAMILIA DE RETINOBLASTOMA (pRb, p107 Y p130) EN LOS PROCESOS DE PROLIFERACIÓN, DIFERENCIACIÓN Y CARCINOGÉNESIS DE PIEL DE RATÓN SERGIO RUIZ MACÍAS MADRID, 2004 El trabajo experimental presentado en esta memoria se ha realizado en el Departamento de Daño, Reparación e Ingeniería Tisular en Epitelios del CIEMAT bajo la co-dirección de los Doctores Jesús M. Paramio González y José Luis Jorcano Noval A mi Familia AGRADECIMIENTOS. Parece que fue ayer el día en que empecé a trabajar en el CIEMAT. Sin embargo no fue ayer, sino que fue allá por Julio de 1998. Hoy, 6 años después, hay mucha gente a la que debo agradecer el resultado de todo mi trabajo. En primer lugar, a mis dos co-directores de Tesis. Por un lado, a José Luis Jorcano que confió en mí y me integró en su grupo (aún habiéndonos conocido en tan extrañas circunstancias). Por otro, a Jesús M. Paramio, mi alma pater durante todo este período. A él le debo todo lo que soy, científicamente hablando, por supuesto. Realmente, no sé que harás sin mí…bueeeno, venga, ni yo sin ti (je, je). A Carmen, a la que agradezco todo el esfuerzo que realizó en enseñarme durante los duros momentos del principio y por supuesto, por estar siempre ahí cuando la he necesitado. Al resto de componentes de mi grupo: a Hugo: por ser tan buen amigo y tener siempre un chistecillo malo en la cabeza preparado para ser contado; a Miren, que me ayudó con toda la parte de carcinogénesis ya que yo tenía poca idea; a Maria Fernanda, sangre nueva en el grupo, a la que agradezco que siga con todo el trabajo que he empezado (por cierto, no se dice zell zaikel); a Pilar por su apoyo técnico en todo momento. A mis compañeros coetáneos de Tesis: a Elenita, que es entusiasmo puro por todo aquello en lo que cree; a Javi, al que admiro mucho por los pasos que va dando en este mundo (¡¡ya eres papá¡¡); a Paula, por estar siempre dispuesta a tomar la penúltima; a Ángela, por intentar siempre arreglar el mundo (por cierto, la próxima debes ser tú). A Marta G, que es mi ojito derecho y a la que quiero un montón. A Marta C, Mariajo e Isa, por las que siento una debilidad especial. A todos los demás del despachito de arriba y abajo, Laura, Vanessa, Rodolfito, Sandra, Toñi, Alejo, Martín, Blanca, Almudena y Ramón por hacer más divertido este laboratorio. A Sole y a Mandi que aunque no están en los despachitos, también son lo mejor de lo mejor (¿probaré alguna vez las croquetas de la Sole?). A Eva y Martita, que han sido y son muy especiales para mi. Al resto de gente del grupo, que están o que han estado y que me ayudado en todo lo que he necesitado, Llanos, Ángel, Angus, Fer, Marce, Manu, Paloma, Rodolfo y Marta I. A Isabel, por haberme hecho tantos y tantos cortes y por ser como mi segunda madre. A todo el fondo sur, Maruja, Isra, Manuel, Teresa, Jaco (a ver si preparamos los medios alguna vez…), Guille, José Carlos, Bea, Elena, Susana G, Susana N, Rosa, Óscar, Mª Eugenia, Ariana, África, Mª Luz, Florencio, Sergio y Juan. Al despacho de pedidos, Elena, MariLo y Aurora por tener esa reserva espiritual siempre preparada y que me salvó más de una vez. A todo el personal del animalario, en especial a Jesús, que aunque no hace nada más que quitarme espacio, en el fondo es que tiene que hacerlo (pero ni uno más ¿eh?). A los secretarios, Ludi, que me ha sacado de tantos líos que ni me acuerdo y Miguel (este año no nos salva ni el gordo, ¡Hala Madrid¡). A XiaoLing, Scott, Carla y Reneé sin los cuales mi estancia en Amsterdam hubiera sido muy diferente. A Marc y Jos por haberme inculcado la parte crítica de la ciencia y a Ralphie por su incomparable humor. A Ton y al resto de la quinta planta del NKI donde pasé todos esos largos meses en Amsterdam. A mis antiguas compañeras del labo de Bioquímica de la Complu, Lola, Ana, MariCarmen, Inma, Eduardo y en especial a Begoña, que fue la primera que me enseñó de qué va esto de la ciencia. A todo el resto de la gente que ha vivido mi Tesis un poco más lejos: A mis compañeros de piso, George (que perdió el tren hace mucho), Santi (que perdió la cabeza por allá en las tierras gallegas), y Diego (al que perdimos hace tiempo) con los que convivir es toda una aventura (¿se acabarán los guisantes de una vez?). Por supuesto, al resto de Proclaimers, con los que he vivido tantas y tantas cosas y todavía espero hacerlo, Emilio, Saúl, Javi, Pascual, Pedrito, Ortuño, Nacho, Juanfri, JuananTorres, Alvarito y Conguito. Al resto de mis amigos del Chami con los que tengo tantas anécdotas, en especial a Merlín, Maese… Todo hay que decirlo, ninguno de estos sabe distinguir una ameba de un ratón. A tres de mis mejores amigos, David, Pollo y Ángel. A toda mi Tuna, Pat, Usi, Tote, Luis, Juli, Fran y todos los demás, con la que he aprendido mucho de lo que necesitaba saber sobre la vida. ¿Qué haría yo sin esos ensayos eternos hasta las mil de la madrugada solo por el mero placer de cantar y pasar un rato divertido?. A mis amigos de Ciudad-Real, Fer, Iván, Alberto, Jota, Rosa, Lucía, César, Isabelle y Olga. A toda mi gran familia, en especial a mi tío Carlos que siempre se preocupó por intentar comprender algo de lo que hacía y nunca perdió el interés en escucharme; a mi tía Pili con la que he compartido todos estos años en Madrid; a mis abuelas Isabel y Mercedes, donde quiera que estén, y que hicieron tanto por mi educación; a mi tía Rosi, por enseñarme a vivir la vida; a mis tíos Maribel y Sireno, que tanto han hecho por nosotros. A mis hermanos, con los que aunque la convivencia ha sido muy dura, ha merecido la pena; os quiero un montón. A mis padres, que siempre me han proporcionado, dentro de sus limitadas posibilidades, lo mejor de todas las cosas. En especial, a mi madre, a la que admiro en todo lo que hace ¡¡Gracias por luchar por mi en todo momento¡¡. A todos, ¡¡¡¡Gracias¡¡¡¡ __________________________________________________________________________ Abreviaturas % Porcentaje. ºC Grados Celsius. mg, mm, mm Microgramo, micrometro, milímetro. ml, mM Microlitro, micromolar. ADN Ácido DesoxirriboNucleico. ADNc Ácido DesoxirriboNucleico complementario. APC Del inglés, Adenomatous Polyposis Coli. ARN Ácido RiboNucleico. ARNm Ácido RiboNucleico mensajero. BrdU Bromo-deoxi Uridina. BMP Del inglés, Bone Morphogenetic Protein, Proteína morfogénica de médula. BSA Del inglés, Bovine Serum Albumine, Seroalbúmina bovina. Ca2+ Iones de calcio. CBP Del inglés, CREB Binding Protein, Proteína de unión al factor CREB. C/EBP Del inglés, CCAAT/Enhancer Binding Protein, Proteína de unión a la secuencia activadora CCAAT. CDK Del inglés, Cycling-Dependent Kinases, Quinasas dependientes de ciclinas. CKI Del inglés, Cycling-Dependent Kinases Inhibitors, Inhibidores de quinasas dependientes de ciclinas. com común. DAB DiAminoBencidina. DAPI Del inglés, 4, 6 DiAmidin-2-Phenyl-Indole, 4,6 diamidino-2-fenil-indol. dCTP Del inglés, deoxiCitidine TriPhosphate, Deoxicitidina trifosfato. dUTP Del inglés, deoxiUridine TriPhosphate, Deoxuridina trifosfato. DMBA 7, 12-DiMetilBenz(a)Antraceno. DMEM Del inglés, Dulbecco's Modified Eagle Medium, Medio de cultivo Eagle modificado por Dulbecco. dNTP Del inglés, deoxiNucleotidil TriPhosphate, Deoxinucleotidil trifosfato. dpc días post-coitum. EDA Del inglés, EctoDysplasin A, Ectodisplasina A. EDAR Del inglés, EctoDysplasin A Receptor, Receptor de la ectodisplasina A. EDTA Del inglés, Ethylen-Diamin Tetra-Acetate, Etilén-diamino-tetra-acetato. EGF Del inglés, Epidermal Growth Factor, Factor de crecimiento epidérmico. EMEM Del inglés, Essential Minimum Eagle Medium, Medio mínimo esencial de Eagle. EMSA Del inglés, ElectroMobility Shift Assays, Ensayos de mobilidad electroforética. FACS Del inglés, Fluorescent Activated Cell Sorting, Separación celular dependiente de fluorescencia. FITC Del inglés, Fluorescein IsoThiCyanate, Isotiocianato de fluoresceína. __________________________________________________________________________ Abreviaturas Fig Figura. FGF Del inglés, Fibroblast Growth Factor, Factor de crecimiento de fibroblastos. GBD Del inglés, GSK3b Binding Domain, Dominio de unión a GSK3 b. GFP Del inglés, Green Fluorescent Protein, Proteína verde fluorescente. GS -1 Del inglés, Glycogen Sintetase-1, Glicógeno sintetasa-1. GSK3 b Del inglés, Glycogen Sintetase Kinase 3b, Quinasa de la glucógeno sintetasa 3b. GST Del inglés, Glutation-S-Transferase, Transferasa S del glutation. HaCaT Del inglés, Human adult Calcium Temperature. H2B Del inglés, Histone 2B, Histona 2B. HBP Del inglés, HMG Box-containing Protein 1, Proteína 1 que contiene un dominio de unión HMG. Hepes Del inglés, N2-HydroxyEthylPiperazine-N'-2-EthaneSulphonic acid, Ácido N2-hidroxietilpiperacin-N'-2-etanosulfónico. HGF Del inglés, Hepacyte Growth Factor, Factor de crecimiento de hepatocitos. H&E Hematoxilina/ Eosina. HPV Del inglés, Human Papiloma Virus, Virus de papiloma humano. JNK Del inglés, JuN Kinase, Quinasa del factor Jun. K Del inglés, Keratin, Queratina. Mut Mutación en el gen descrito. neo neomicina. NFkB Del inglés, Nuclear Factor kB, Factor nuclear kB. NOD/SCID Del inglés, Non-Obese Diabetic/Severe Combined Immunodeficiency Disease, ratón diabético no obeso portador de inmunodeficiencia combinada severa.
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