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Los mutantes PTEN asociados al cáncer actúan de manera dominante negativa para suprimir la función de la proteína
Antonella Papa1, Lixin Wan2, Massimo Bonora3
1Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Cell
|April 29, 2014
Resumen
La proteína PTEN forma dímeros para regular su actividad. Las mutaciones de PTEN asociadas al cáncer pueden afectar esta función, lo que lleva a una mayor susceptibilidad tumoral y efectos similares a la pérdida completa de PTEN.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Oncología Oncología.
- La bioquímica es la bioquímica.
Sus antecedentes:
- PTEN (homólogo de la fosfatasa y la tensina) es un supresor tumoral crítico.
- La disfunción PTEN está implicada en varios tipos de cáncer.
- Comprender la regulación de PTEN es vital para la terapia del cáncer.
Objetivo del estudio:
- Investigar el papel de la homodimerización y heterodimerización de PTEN con formas mutantes en la regulación de la actividad de PTEN.
- Para dilucidar las consecuencias in vivo de las mutaciones PTEN asociadas al cáncer.
- Para diferenciar los efectos de la pérdida de PTEN de las mutaciones de PTEN en la patogénesis del cáncer.
Principales métodos:
- Ensayos bioquímicos para estudiar la homodimerización de PTEN y la actividad de la lipida fosfatasa.
- Generación y análisis de modelos de ratones Pten knockin con mutaciones específicas asociadas al cáncer (PtenC124S, PtenG129E).
- Evaluación de la activación de la vía PI3-K/Akt en células y tejidos de ratones Pten knockin.
Principales resultados:
- El PTEN homodimeriza en una conformación activa, desfosforilando el fosfatidilinositol (3,4,5) -trisfosfato (PtdIns(3,4,5) P3).
- Los mutantes de PTEN catalíticamente inactivos heterodimerizan con el PTEN de tipo silvestre, inhibiendo su actividad de manera dominante-negativa.
- Los ratones knockin de Pten con mutaciones heterocigotas mostraron una mayor sensibilidad a la activación de PI3-K/Akt y una mayor predisposición tumoral, imitando la pérdida completa de Pten.
Conclusiones:
- Las mutaciones de PTEN y la pérdida completa de PTEN son mecanismos distintos en el desarrollo del cáncer.
- La dimerización de PTEN es un mecanismo regulador clave para su función supresora del tumor.
- Las mutaciones de PTEN asociadas al cáncer pueden actuar de manera dominante, afectando la actividad de PTEN de tipo salvaje y promoviendo la tumorigénesis.
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