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La actividad oncogénica de Cdc6 a través de la represión del locus INK4/ARF
Susana Gonzalez1, Peter Klatt, Sonia Delgado
1Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), E-28029 Madrid, Spain.
Nature
|March 31, 2006
Resumen
La Cdc6 sobreexpresada reprime el locus supresor de tumores INK4/ARF al formar heterocromatina, promoviendo el desarrollo del cáncer. Este mecanismo involucra el elemento regulador RD ((INK4/ARF) y vincula Cdc6 a la inmortalización y transformación celular.
Área de la Ciencia:
- Oncología Oncología.
- Biología Molecular Biología Molecular
- La epigenética es la epigenética.
Sus antecedentes:
- El locus INK4/ARF, que codifica los supresores de tumores cruciales (p15INK4b, ARF, p16INK4a), es frecuentemente inactivado en los cánceres humanos.
- Los mecanismos que regulan la expresión del locus INK4/ARF siguen siendo en gran medida desconocidos.
Objetivo del estudio:
- Investigar los mecanismos regulatorios que rigen el lugar INK4/ARF.
- Explorar el papel de Cdc6 en la regulación de la expresión génica del supresor tumoral.
Principales métodos:
- Identificación de un origen de replicación del ADN y un elemento no codificante conservado (RD(INK4/ARF)) en el locus INK4/ARF.
- La heterocromatinización mediada por interferencia de ARN de RD ((INK4/ARF) para evaluar su función reguladora.
- Análisis de los niveles de expresión de Cdc6 y su correlación con el silenciamiento del locus INK4/ARF y los fenotipos de cáncer.
Principales resultados:
- Un complejo multiproteínico que incluye Cdc6, Orc2 y MCMs se ensambla en el origen de replicación identificado dentro del elemento RD ((INK4/ARF).
- La heterocromatinización de RD ((INK4/ARF) conduce a la represión transcripcional del locus INK4/ARF.
- Los altos niveles de Cdc6 inducen la represión dependiente de RD ((INK4/ARF), el reclutamiento de la histona desacetilasa, la formación de heterocromatina y la disminución de la expresión de los supresores de tumores INK4/ARF.
- La sobreexpresión de Cdc6 se correlaciona con la inmortalización celular, la transformación neoplásica y los niveles reducidos de p16INK4a en los carcinomas pulmonares.
Conclusiones:
- La expresión aberrante de Cdc6 reprime oncogénicamente el locus INK4/ARF a través del elemento RD ((INK4/ARF).
- Cdc6 actúa como un nuevo regulador de la expresión génica del supresor tumoral a través de mecanismos epigenéticos.
- Esta vía pone de relieve un nuevo mecanismo por el cual Cdc6 contribuye al desarrollo del cáncer.
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