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In Vitro SUMOylation Assay to Study SUMO E3 Ligase Activity
Published on: January 29, 2018
Se requiere un subprograma transcripcional dependiente de la SUMOilación para la tumorigénesis impulsada por Myc
Jessica D Kessler1, Kristopher T Kahle, Tingting Sun
1Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Science (New York, N.Y.)
|December 14, 2011
Resumen
Dirigirse a la enzima activadora de SUMO (SAE1/2) causa letalidad sintética en los cánceres impulsados por Myc. La inhibición de SAE1/2 interrumpe el funcionamiento de Mycc.
Área de la Ciencia:
- Oncología Oncología.
- Biología Molecular Biología Molecular
- Genética La genética.
Sus antecedentes:
- Myc es un factor de transcripción oncogénico clave a menudo desregulado en los cánceres humanos.
- La identificación de vías que apoyan el programa oncogénico de Myc es crucial para el desarrollo de terapias dirigidas.
Objetivo del estudio:
- Para identificar los genes que son sintéticamente letales con Myc utilizando una pantalla de interferencia de ARN de todo el genoma.
- Investigar el papel de la enzima activadora de SUMO (SAE1/2) en los cánceres impulsados por Myc.
Principales métodos:
- Pantalla de interferencia de ARN en todo el genoma para identificar genes letales sintéticos de Myc.
- Inactivación de SAE2 para observar los efectos en la hiperactivación de Myc.
- Análisis de los conmutadores Myc dependientes de la SUMOilación (genes SMS) y su papel en la función del huso mitótico.
- Evaluación del requisito SAE2 para el crecimiento tumoral dependiente de Myc en ratones.
- Análisis de la expresión génica de los cánceres de mama humanos con Myc-high.
Principales resultados:
- Se descubrió un papel para la enzima activadora de SUMO (SAE1/2) como un gen letal sintético de Myc.
- La pérdida de la actividad enzimática SAE1/2 conduce a la letalidad sintética con Myc.
- La inactivación de SAE2 causa catástrofe mitótica y muerte celular tras la hiperactivación de Myc.
- La inhibición de SAE2 cambia el programa de transcripción de Myc de la activación a la represión.
- Un subconjunto de interruptores Myc dependientes de la SUMOilación (genes SMS) es esencial para la función del huso mitótico y el programa oncogénico de Myc.
- Se requiere SAE2 para el crecimiento de tumores dependientes de Myc en ratones.
- La baja abundancia de SAE1 y SAE2 en los cánceres de mama humanos se correlaciona con una mayor supervivencia libre de metástasis.
Conclusiones:
- La inhibición de la SUMOilación, específicamente dirigida a SAE1/2, presenta una estrategia terapéutica potencial para los cánceres impulsados por Myc.
- Comprender el mecanismo de interrupción Myc dependiente de la SUMOilación ofrece información sobre la biología del cáncer.
- Dirigirse a SAE1/2 puede ser una vía prometedora para el tratamiento de tumores malignos humanos dependientes de Myc.
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