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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
El silenciamiento de la heterocromatina de los genes diana de p53 por una pequeña proteína viral
Conrado Soria1, Fanny E Estermann, Kristen C Espantman
1Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, California 92037-1099, USA.
Nature
|August 27, 2010
Resumen
La proteína E4-ORF3 del adenovirus silencia el supresor tumoral p53 (también conocido como TP53) a través de un mecanismo epigenético. Esta nueva vía, independiente de la estabilización de p53, implica la formación de una estructura nuclear que bloquea la unión de p53 al ADN.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- La epigenética es la epigenética.
- Virología Virología.
Sus antecedentes:
- El supresor tumoral p53 (TP53) es crucial para prevenir el cáncer y la replicación viral, por lo general se inactiva en la mayoría de los cánceres.
- La transcripción mediada por p53 está generalmente relacionada con su estabilización tras el daño del ADN o la activación de oncogenes.
- La proteína del adenovirus E1B-55k inactiva p53 por degradación, lo que constituye la base para las actuales terapias contra el cáncer selectivas de p53.
Objetivo del estudio:
- Para dilucidar el mecanismo por el cual la proteína del adenovirus E4-ORF3 inactiva la transcripción activada por p53.
- Para investigar el papel de las modificaciones epigenéticas en la inactivación de p53 durante la infección por adenovirus.
- Explorar nuevas estrategias para las terapias virales oncolíticas selectivas p53.
Principales métodos:
- Investigó la interacción entre el adenovirus E4-ORF3 y p53.
- Se utilizaron ensayos de inmunoprecipitación de cromatina para analizar las modificaciones histónicas en los promotores objetivo de p53.
- Actividad evaluada de unión y transcripción del p53-ADN en presencia de E4-ORF3.3.
Principales resultados:
- La proteína E4-ORF3 del adenovirus induce de novo la formación de heterocromatina H3K9me3 en los promotores objetivo de p53.
- Este silenciamiento epigenético impide la unión al ADN-p53, independientemente de la fosforilación y la estabilización del p53.
- E4-ORF3 forma una estructura nuclear selectiva que inactiva p53, distinto de la degradación mediada por E1B-55k.
Conclusiones:
- El adenovirus E4-ORF3 emplea un mecanismo epigenético dominante para silenciar la p53, independientemente de la estabilización de la p53.
- Este hallazgo revela una nueva vía para la inactivación de p53 en el cáncer y las infecciones virales.
- El estudio proporciona información para el desarrollo de terapias virales oncolíticas p53 selectivas avanzadas dirigidas al silenciamiento epigenético.
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