PROTEIN DEGRADATION MEDIATED BY UBIQUITINATION IN CANCER: THERAPEUTIC IMPLICATIONS (Q3134321): Difference between revisions
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(Created claim: summary (P836): THE VIABILITY OF CELLS DEPENDS ON THE PROPER FUNCTIONING OF A SET OF NETWORKED MOLECULAR MECHANISMS THAT CONTROL BIOLOGICAL PROCESSES, RANGING FROM PROLIFERATION AND DIFFERENTIATION TO CELL DEATH. THE UBIQUITINATION OF PROTEINS ALLOWS RAPID DEGRADATION OF THE REGULATORY COMPONENTS OF THESE MECHANISMS, CONTRIBUTING TO THE PRECISE SYNCHRONISATION OF COMPLEX CELLULAR PROCESSES. GIVEN THIS CRITICAL FUNCTION, UBIQUITINACION MACHINERY IS OFTEN UNREGUL...) |
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PROTEIN DEGRADATION MEDIATED BY UBIQUITINATION IN CANCER: THERAPEUTIC IMPLICATIONS | |||
Revision as of 12:31, 12 October 2021
Project Q3134321 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | PROTEIN DEGRADATION MEDIATED BY UBIQUITINATION IN CANCER: THERAPEUTIC IMPLICATIONS |
Project Q3134321 in Spain |
Statements
106,480.0 Euro
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133,100.0 Euro
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80.0 percent
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1 January 2015
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30 September 2018
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UNIVERSIDAD DE SEVILLA
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37°23'19.07"N, 5°59'43.22"W
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41091
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LA VIABILIDAD DE LAS CELULAS DEPENDE DEL BUEN FUNCIONAMIENTO DE UN CONJUNTO DE MECANISMOS MOLECULARES CONECTADOS EN RED QUE CONTROLAN LOS PROCESOS BIOLOGICOS, QUE VAN DESDE LA PROLIFERACION Y LA DIFERENCIACION A LA MUERTE CELULAR. LA UBIQUITINACION DE LAS PROTEINAS PERMITE DEGRADAR RAPIDAMENTE LOS COMPONENTES REGULADORES DE ESTOS MECANISMOS, CONTRIBUYENDO A LA PRECISA SINCRONIZACION DE LOS COMPLEJOS PROCESOS CELULARES. DADA ESTA CRITICA FUNCION, LA MAQUINARIA DE UBIQUITINACION ESTA A MENUDO DESREGULADA EN NUMEROSOS PROCESOS PATOLOGICOS, INCLUIDO EL CANCER. POR TANTO, LA COMPRENSION DE LAS BASES MOLECULARES DE LA DEGRADACION DE LAS PROTEINAS IMPLICADAS EN LA TRANSFORMACION MALIGNA CONDUCIRA NO SOLO A NUEVOS AVANCES EN EL CONOCIMIENTO DE LA BIOLOGIA DEL CANCER, SINO TAMBIEN A NUEVAS Y MAS EFICACES TERAPIAS CONTRA LOS TUMORES. NUESTRO PROYECTO DE INVESTIGACION SE CENTRA EN EL ESTUDIO DE LAS PROTEINAS QUE SON UBIQUITINADAS POR LAS E3 LIGASAS SCF, CONCRETAMENTE POR SCFBETATRCP Y/O SCFFBXW7. LA IDEA ULTIMA ES LA COMPRENSION DE LOS MECANISMOS MOLECULARES A TRAVES DE LOS CUALES LAS UBIQUITIN LIGASAS SCF CONTROLAN LOS PARAMETROS FUNDAMENTALES DE LA VIDA CELULAR, ES DECIR, EL CRECIMIENTO, LA PROLIFERACION Y LA SUPERVIVENCIA Y DIFERENCIACION. A MEDIDA QUE DESCUBRIMOS LOS DETALLES DE COMO LA DEGRADACION DE LAS PROTEINAS REGULADORAS, FISCALIZADAS POR EL SISTEMA DE UBIQUITINACION, CONTROLA LAS VIAS CELULARES FUNDAMENTALES, INTEGRAMOS ESTOS PUNTOS DE VISTA DE INVESTIGACION BASICA CON EL ESTUDIO DE LOS CANCERES HUMANOS. EN NUESTROS ESTUDIOS INICIALES, UTILIZAMOS TANTO RASTREOS MASIVOS EMPLEANDO EL SISTEMA DEL DOBLE HIBRIDO EN LEVADURA, COMO LA IDENTIFICACION DE LAS PROTEINAS QUE INTERACCIONAN MEDIANTE APROXIMACIONES PROTEOMICAS. POSTERIORMENTE, NOS HEMOS CENTRADO EN LA ELUCIDACION DE LA FUNCION BIOLOGICA DE ALGUNAS DE LAS REGULACIONES OBTENIDAS. ENTRE ELLAS, ESTUDIAMOS EL PAPEL DE LA ESTABILIDAD DE PLK1 Y CDK1, DOS QUINASAS IMPLICADAS EN LA REGULACION DEL CICLO CELULAR Y EL CANCER. EN CONCRETO ANALIZAMOS COMO SCFFBXW7 MODULA EL PUNTO DE CONTROL DE LA FASE S TRAS DAÑOS EN EL ADN A TRAVES DE PLK1 Y COMO SCFBETATRCP MEDIA EN LA DEGRADACION DE CDK1 VIA LISOSOMA Y LA INFLUENCIA DE LA ACUMULACION DE ESTA PROTEINA EN TUMORES. AHORA PRESENTAMOS UN NUEVO PROYECTO QUE TIENE COMO OBJETIVO ESTUDIAR LA REGULACION DE LA DEGRADACION DE LAS CITADAS QUINASAS, ANALIZAR EL POSIBLE USO DE LA CANTIDAD DE CDK1 TRAS AGENTES QUE DAÑEN EL ADN COMO MARCADOR PREDICTIVO DE LA EVOLUCION DE LOS TUMORES, INVESTIGAR LA DEGRADACION DEL SUPRESOR TUMORAL P53 POR SCFFBXW7 E INTENTAR CARACTERIZAR OTROS SUSTRATOS IDENTIFICADOS EN LOS PROYECTOS ANTERIORES. EL ABORDAJE EXPERIMENTAL SEGUIDO HA SIDO Y ESTA SIENDO MULTIDISCIPLINAR, EMPLEANDO TANTO TECNICAS BIOQUIMICAS, MOLECULARES Y CELULARES, COMO ENSAYANDO LAS CONCLUSIONES EXTRAIDAS EN MUESTRAS DE PACIENTES. PRUEBA DE ELLO ES QUE UNA PARTE IMPORTANTE DEL PROYECTO QUE SE PRESENTA ESTA DEDICADA A LA IMPLEMENTACION DEL USO DE CDK1 COMO MARCADOR PARA PREDECIR LA BONDAD DE UNA DETERMINADA TERAPIA EN EL TRATAMIENTO DE LOS PACIENTES INDIVIDUALES DE CANCER. ADEMAS, NOS PROPONEMOS SEGUIR ESTUDIANDO LA REGULACION DE LA DEGRADACION DE OTRAS PROTEINAS CON LA IDEA DE EXTRAPOLAR LOS RESULTADOS A LA APLICACION MEDICA. (Spanish)
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THE VIABILITY OF CELLS DEPENDS ON THE PROPER FUNCTIONING OF A SET OF NETWORKED MOLECULAR MECHANISMS THAT CONTROL BIOLOGICAL PROCESSES, RANGING FROM PROLIFERATION AND DIFFERENTIATION TO CELL DEATH. THE UBIQUITINATION OF PROTEINS ALLOWS RAPID DEGRADATION OF THE REGULATORY COMPONENTS OF THESE MECHANISMS, CONTRIBUTING TO THE PRECISE SYNCHRONISATION OF COMPLEX CELLULAR PROCESSES. GIVEN THIS CRITICAL FUNCTION, UBIQUITINACION MACHINERY IS OFTEN UNREGULATED IN NUMEROUS PATHOLOGICAL PROCESSES, INCLUDING CANCER. THEREFORE, THE UNDERSTANDING OF THE MOLECULAR BASES OF THE DEGRADATION OF PROTEINS INVOLVED IN MALIGNANT TRANSFORMATION WILL LEAD NOT ONLY TO NEW ADVANCES IN THE KNOWLEDGE OF CANCER BIOLOGY, BUT ALSO TO NEW AND MORE EFFECTIVE THERAPIES AGAINST TUMORS. OUR RESEARCH PROJECT FOCUSES ON THE STUDY OF PROTEINS THAT ARE UBIQUITINATED BY E3 LIGASE SCF, SPECIFICALLY BY SCFBETATRCP AND/OR SCFFBXW7. THE ULTIMATE IDEA IS THE UNDERSTANDING OF THE MOLECULAR MECHANISMS THROUGH WHICH UBIQUITIN LIGASES SCF CONTROL THE FUNDAMENTAL PARAMETERS OF CELL LIFE, I.E. GROWTH, PROLIFERATION AND SURVIVAL AND DIFFERENTIATION. AS WE DISCOVER THE DETAILS OF HOW THE DEGRADATION OF REGULATORY PROTEINS, CONTROLLED BY THE UBIQUITINACION SYSTEM, CONTROLS FUNDAMENTAL CELLULAR PATHWAYS, WE INTEGRATE THESE BASIC RESEARCH VIEWS WITH THE STUDY OF HUMAN CANCERS. IN OUR INITIAL STUDIES, WE USE BOTH MASSIVE TRACES USING THE DOUBLE-HYBRID SYSTEM IN YEAST, AND THE IDENTIFICATION OF PROTEINS THAT INTERACT THROUGH PROTEOMIC APPROACHES. SUBSEQUENTLY, WE HAVE FOCUSED ON THE ELUCIDACION OF THE BIOLOGICAL FUNCTION OF SOME OF THE REGULATIONS OBTAINED. AMONG THEM, WE STUDIED THE ROLE OF THE STABILITY OF PLK1 AND CDK1, TWO KINASES INVOLVED IN CELL CYCLE REGULATION AND CANCER. IN PARTICULAR, WE ANALYSED HOW SCFFBXW7 MODULATES THE CONTROL POINT OF PHASE S AFTER DNA DAMAGE THROUGH PLK1 AND AS MEAN SCFBETATRCP IN THE DEGRADATION OF CDK1 VIA LYSOSOMA AND THE INFLUENCE OF THE ACCUMULATION OF THIS PROTEIN IN TUMORS. NOW WE PRESENT A NEW PROJECT THAT AIMS TO STUDY THE REGULATION OF THE DEGRADATION OF THE AFOREMENTIONED KINASES, ANALYSE THE POSSIBLE USE OF THE AMOUNT OF CDK1 AFTER AGENTS THAT DAMAGE DNA AS A PREDICTIVE MARKER OF THE EVOLUTION OF TUMORS, INVESTIGATE THE DEGRADATION OF TUMOR SUPPRESSOR P53 BY SCFFBXW7 AND TRY TO CHARACTERISE OTHER SUBSTRATES IDENTIFIED IN PREVIOUS PROJECTS. THE EXPERIMENTAL APPROACH FOLLOWED HAS BEEN AND IS BEING MULTIDISCIPLINARY, EMPLOYING BOTH BIOCHEMICAL, MOLECULAR AND CELLULAR TECHNIQUES, AS WELL AS TESTING THE CONCLUSIONS DRAWN IN PATIENT SAMPLES. EVIDENCE OF THIS IS THAT AN IMPORTANT PART OF THE PROJECT PRESENTED IS DEDICATED TO THE IMPLEMENTATION OF THE USE OF CDK1 AS A MARKER TO PREDICT THE GOODNESS OF A GIVEN THERAPY IN THE TREATMENT OF INDIVIDUAL CANCER PATIENTS. IN ADDITION, WE INTEND TO CONTINUE STUDYING THE REGULATION OF THE DEGRADATION OF OTHER PROTEINS WITH THE IDEA OF EXTRAPOLATING THE RESULTS TO THE MEDICAL APPLICATION. (English)
12 October 2021
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Sevilla
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Identifiers
SAF2014-53799-C2-1-R
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