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El papel transcripcional de la ciclina D1 en el desarrollo revelado por una pantalla genética-proteómica
Frédéric Bienvenu1, Siwanon Jirawatnotai, Joshua E Elias
1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Nature
|January 22, 2010
Resumen
La ciclina D1, una proteína del ciclo celular, también funciona en la transcripción durante el desarrollo del ratón. Recluta CBP para el promotor del gen Notch1, regulando su expresión e impactando la proliferación de células progenitoras de la retina.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Biología del desarrollo Biología del desarrollo.
- Investigación del cáncer Investigación del cáncer.
Sus antecedentes:
- La ciclina D1 es un regulador clave del ciclo celular que con frecuencia se sobreexpresa en los cánceres humanos.
- Las funciones completas de la ciclina D1 en el desarrollo normal y la oncogénesis siguen siendo en gran medida desconocidas.
Objetivo del estudio:
- Investigar las funciones in vivo de la ciclina D1 más allá de sus funciones en el ciclo celular.
- Identificar nuevas proteínas de unión a la ciclina D1 y objetivos transcripcionales utilizando un enfoque genético-proteómico.
Principales métodos:
- Desarrollo de modelos de ratones knock-in de ciclina D1 etiquetados con Flag y hemaglutinina.
- Espectrometría de masas de alto rendimiento para identificar las proteínas que interactúan con la ciclina D1.
- Inmunoprecipitación de cromatina acoplada al microarray de ADN (ChIP-chip) para el análisis de ubicación de todo el genoma.
Principales resultados:
- Se descubrió que la ciclina D1 se une a los promotores de genes transcritos activamente durante el desarrollo del ratón.
- En el desarrollo de las retinas, la ciclina D1 recluta la proteína de unión CREB (CBP) al promotor del gen Notch1.
- La pérdida de ciclina D1 condujo a una reducción en el reclutamiento de CBP, una disminución en la expresión de Notch1 y una disminución en la proliferación de células progenitoras de la retina.
Conclusiones:
- La ciclina D1 posee una importante función transcripcional in vivo en el desarrollo del ratón, independiente de su papel en el ciclo celular canónico.
- El enfoque "genético-proteómico" identificado es una herramienta versátil para estudiar las funciones in vivo de varias proteínas.
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