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La beta-catenina regula la expresión de la ciclina D1 en las células del carcinoma de colon
1University of California, San Francisco, School of Medicine, Cancer Research Institute, 94143-0128, USA.
Nature
|April 14, 1999
Resumen
Las mutaciones en el gen de la poliposis coli adenomatosa (APC) conducen a la acumulación de beta-catenina, impulsando el cáncer de colon. Esta beta-catenina activa la ciclina D1, promoviendo la progresión del ciclo celular y el crecimiento tumoral.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Genética del cáncer Genética del cáncer.
- El Reglamento del Ciclo Celular.
Sus antecedentes:
- Las mutaciones en el gen supresor de tumores de la poliposis coli adenomatosa (APC) son comunes en los cánceres de colon humanos.
- La pérdida de la función de la APC conduce a la acumulación de beta-catenina, que se observa en varios tipos de cáncer, incluidos los carcinomas de colon, melanoma y hígado.
- La beta-catenina acumulada interactúa con los factores de transcripción TCF / LEF, activando los genes diana.
Objetivo del estudio:
- Investigar el papel de la beta-catenina en la activación del promotor de la ciclina D1.
- Para determinar si los sitios de unión TCF/LEF son esenciales para la activación de la ciclina D1 mediada por la beta-catenina.
- Para dilucidar el impacto de la inhibición mutante de la beta-catenina y el TCF en la expresión de la ciclina D1 y la progresión del ciclo celular.
Principales métodos:
- Análisis del efecto de la beta-catenina en la actividad del promotor de la ciclina D1.
- Identificación de las secuencias esenciales de unión TCF/LEF dentro del promotor de ciclina D1.
- Evaluación de los niveles de ARNm y proteínas de la ciclina D1 en las células que expresan la beta-catenina mutante.
- Evaluación de los efectos dominantes negativos de TCF en la expresión génica y la detención del ciclo celular.
Principales resultados:
- La beta-catenina activa la transcripción desde el promotor de la ciclina D1, lo que requiere sitios de unión TCF/LEF.
- La beta-catenina mutante conduce a altos niveles constitutivos de ARNm y proteína de la ciclina D1.
- La p21ras oncogénica también mejora la transcripción de la ciclina D1 a través de los sitios de unión de Ets o CREB.
- El TCF negativo dominante inhibe la expresión de la ciclina D1, causando la detención del ciclo celular G1, que es rescatada por la reexpresión de la ciclina D1.
Conclusiones:
- La acumulación anormal de beta-catenina, impulsada por mutaciones de APC, contribuye a la transformación neoplásica.
- La beta-catenina promueve el cáncer al inducir la acumulación de ciclina D1, lo que lleva a la desregulación del ciclo celular.
- Dirigirse a las vías de beta-catenina o TCF puede ofrecer estrategias terapéuticas para los cánceres con señalización aberrante de beta-catenina.
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