REVIEWING THE ROLE OF E2F FACTORS IN TUMOR DEVELOPMENT: STUDY OF E2F-EMT CONNECTION (E2F/EPITHELIUM-MESENCHYMA TRANSITION) (Q3138542): Difference between revisions
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43°19'37.56"N, 2°59'4.60"W
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Revision as of 08:39, 9 October 2021
Project Q3138542 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | REVIEWING THE ROLE OF E2F FACTORS IN TUMOR DEVELOPMENT: STUDY OF E2F-EMT CONNECTION (E2F/EPITHELIUM-MESENCHYMA TRANSITION) |
Project Q3138542 in Spain |
Statements
90,750.0 Euro
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181,500.0 Euro
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50.0 percent
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1 January 2019
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31 December 2021
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UNIVERSIDAD DEL PAIS VASCO/EUSKAL HERRIKO UNIBERTSITATEA
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43°19'37.56"N, 2°59'4.60"W
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48054
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LOS FACTORES DE TRANSCRIPCION E2F, LOS INTERACTORES MAS CONOCIDOS DE LA PROTEINA SUPRESORA TUMORAL RETINOBLASTOMA (RB), JUEGAN UN PAPEL CENTRAL EN LA COORDINACION DEL AVANCE DEL CICLO CELULAR A TRAVES DE LA REGULACION PRECISA DE LA EXPRESION GENICA. LA VIA RETINOBLASTOMA (RB)/E2F DEBE ENCONTRARSE INTACTA PARA QUE LA ENTRADA Y PROGRESION DEL CICLO CELULAR SE HAGAN CORRECTAMENTE. ESTA VIA SE ENCUENTRA ALTERADA EN MUCHAS CELULAS TUMORALES HUMANAS A TRAVES DE MULTIPLES MECANISMOS QUE CONDUCEN A LA INACTIVACION DE RB Y LA LIBERACION DE E2F. EN CONSECUENCIA, LA INHIBICION DE LA ACTIVIDAD DE E2F SE HA CONVERTIDO EN UNA ESTRATEGIA TERAPEUTICA PARA EL TRATAMIENTO DEL CANCER. SIN EMBARGO, LOS MECANISMOS POR LOS CUALES LOS FACTORES E2F CONTRIBUYEN A LA MALIGNIDAD NO SE CONOCEN BIEN. DE HECHO, NUESTRO GRUPO Y OTROS HAN MOSTRADO QUE LOS FACTORES E2F PUEDEN DESEMPEÑAR TANTO FUNCIONES DE SUPRESORES TUMORALES COMO DE PROMOTORES TUMORALES, QUE PARECEN DEPENDER DEL CONTEXTO CELULAR ESPECIFICO Y DEL ESTADO DE ACTIVACION DE LAS VIAS QUE CONFLUYEN EN LOS E2F. POR LO TANTO, SE NECESITA UNA MEJOR COMPRENSION DE LA BIOLOGIA DE E2F PARA DISEÑAR ABORDAJES TERAPEUTICOS EFECTIVOS QUE CONVERJAN EN LA ACTIVIDAD DE E2F._x000D_ _x000D_ EN EL CONTEXTO DE NUESTRO PROYECTO SAF ACTUAL, HEMOS OBTENIDO EVIDENCIAS PRELIMINARES QUE INDICAN QUE TRAS LA PERDIDA DE LA ACTIVIDAD DE E2F1 Y E2F2 EN CELULAS DE CANCER COLORRECTAL, SE DESREGULA LA EXPRESION DE UN CONJUNTO DE GENES IMPLICADOS EN LA TRANSICION EPITELIO-MESENQUIMA (EMT), Y LAS CELULAS EXHIBEN SIGNOS DE HALLARSE ATRAVESANDO UN PROCESO DE EMT. SIN EMBARGO, HASTA LA FECHA NO SE HAN EXPLORADO LOS MECANISMOS MEDIANTE LOS CUALES E2F1 Y E2F2 REGULAN LA EXPRESION DE LOS MEDIADORES DE EMT, Y SE DESCONOCE EL GRADO DE IMPLICACION DE E2F1/E2F2 EN LA SUPRESION TUMORAL A TRAVES DE LA MODULACION DEL PROGRAMA EMT. EL OBJETIVO DE ESTE PROYECTO ES DILUCIDAR LOS MECANISMOS POR LOS QUE LAS PROTEINAS E2F MODULAN EL FENOTIPO DE EMT Y EVALUAR EL PAPEL DE LA CONEXION E2F-EMT EN LA MALIGNIDAD TUMORAL, COMBINANDO ENFOQUES DE BIOLOGIA MOLECULAR CLASICA CON LA GENOMICA Y PROTEOMICA DE ALTO RENDIMIENTO, UTILIZANDO TANTO MODELOS IN VITRO COMO IN VIVO. CON ESTE FIN, HEMOS ESTABLECIDO LOS SIGUIENTES OBJETIVOS ESPECIFICOS:_x000D_ _x000D_ 1. DEFINIR LA CONTRIBUCION DE LOS FACTORES E2F A LA REGULACION DE LA EMT. _x000D_ 2. DILUCIDAR LOS MECANISMOS POR LOS QUE E2F MODULAN LA EMT. _x000D_ 3. ESTUDIAR EL FENOTIPO EMT EN LOS MODELOS DE RATON KNOCKOUT PARA E2F. _x000D_ 4. DILUCIDAR LA CONTRIBUCION DE E2F A LA MODULACION DEL POTENCIAL TUMORIGENICO EN MODELOS ANIMALES. _x000D_ _x000D_ CREEMOS QUE NUESTROS HALLAZGOS ARROJARAN LUZ SOBRE LOS MECANISMOS SUBYACENTES A LA REGULACION DE LA EMT POR PARTE DE LOS E2F EN CONDICIONES FISIOLOGICAS Y NEOPLASICAS, LO CUAL CONTRIBUIRA AL DISEÑO DE NUEVOS ENFOQUES TERAPEUTICOS PARA EL CANCER BASADOS EN LA BIOLOGIA DE E2F. (Spanish)
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E2F TRANSCRIPTION FACTORS, THE BEST KNOWN TARGETS OF RETINOBLASTOMA (RB) TUMOR SUPPRESSOR, PLAY A CENTRAL ROLE IN COORDINATING CELL CYCLE PROGRESSION THROUGH THE TIMELY REGULATION OF GENE EXPRESSION. AN INTACT RETINOBLASTOMA (RB)/E2F PATHWAY IS REQUIRED FOR CORRECT ENTRY INTO AND PROGRESSION THROUGH THE CELL CYCLE. THIS PATHWAY BECOMES ABERRANT IN MANY HUMAN TUMOR CELLS THROUGH MULTIPLE MECHANISMS THAT LEAD TO THE INACTIVATION OF RB AND RELEASE OF E2F. CONSEQUENTLY, INHIBITION OF E2F ACTIVITY HAS EMERGED AS A THERAPEUTIC STRATEGY FOR THE TREATMENT OF CANCER. HOWEVER, THE MECHANISMS BY WHICH E2F FACTORS CONTRIBUTE TO MALIGNANCY ARE NOT WELL UNDERSTOOD. IN FACT, OUR GROUP AND OTHERS HAVE REVEALED BOTH TUMOR-SUPPRESSING AS WELL AS TUMOR-PROMOTING ROLES FOR E2F FACTORS, WHICH SEEM TO DEPEND ON THE SPECIFIC CELLULAR CONTEXT AND THE ACTIVATION STATUS OF THE PATHWAYS CONVERGING ON IT. THUS, A BETTER UNDERSTANDING OF E2F BIOLOGY IS NEEDED IN ORDER TO DESIGN EFFECTIVE THERAPEUTIC APPROACHES THAT CONVERGE ON E2F ACTIVITY._x000D_ _x000D_ IN THE CONTEXT OF OUR CURRENT SAF PROJECT, WE HAVE GATHERED PRELIMINARY EVIDENCE INDICATING THAT UPON LOSS OF E2F1 AND E2F2 ACTIVITY IN COLORECTAL CANCER CELLS, THE EXPRESSION OF A SUBSET OF GENES KNOWN TO MEDIATE EPITHELIAL-MESENCHYMAL TRANSITION (EMT) IS DEREGULATED, AND CELLS EXHIBIT SIGNS OF UNDERGOING AN EMT. HOWEVER, THE MECHANISMS BY WHICH E2F1 AND E2F2 REGULATE EMT MEDIATOR EXPRESSION, AND THE CONTRIBUTION OF E2F1/E2F2 TO TUMOR SUPPRESSION THROUGH THE MODULATION OF THE EMT PROGRAM HAVE NOT BEEN EXPLORED TO DATE. THE AIM OF THIS PROJECT IS TO ELUCIDATE THE MECHANISMS BY WHICH E2F PROTEINS MODULATE EMT FEATURES, AND TO ASSESS THE ROLE OF THE E2F-EMT CONNECTION IN TUMOR MALIGNANCY, BY COMBINING CLASSIC MOLECULAR BIOLOGY APPROACHES AND HIGH-THROUGHPUT GENOMICS AND PROTEOMICS, USING BOTH IN VITRO AND IN VIVO MODELS. TO THIS END, WE HAVE ESTABLISHED THE FOLLOWING SPECIFIC AIMS:_x000D_ _x000D_ 1. TO DEFINE THE CONTRIBUTION OF E2F FACTORS TO THE REGULATION OF EMT. _x000D_ 2. TO ELUCIDATE THE MECHANISMS FOR E2F-MEDIATED MODULATION OF EMT. _x000D_ 3. TO STUDY EMT FEATURES IN E2F KNOCKOUT MOUSE MODELS. _x000D_ 4. TO ELUCIDATE THE CONTRIBUTION OF E2F IN MODULATING THE TUMORIGENIC POTENTIAL IN ANIMAL MODELS_x000D_ _x000D_ WE BELIEVE THAT OUR FINDINGS WILL SHED LIGHT ON THE MECHANISMS UNDERLYING EMT REGULATION BY E2FS IN PHYSIOLOGICAL AND NEOPLASTIC CONDITIONS, WHICH WILL CONTRIBUTE TO THE DESIGN OF NOVEL THERAPEUTIC APPROACHES TO CANCER BASED ON E2F BIOLOGY. (English)
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Leioa
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Identifiers
RTI2018-097497-B-I00
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