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La desubiquitinilación y la localización de PTEN están reguladas por una red HAUSP-PML
Min Sup Song1, Leonardo Salmena, Arkaitz Carracedo
1Cancer Genetics Program, Beth Israel Deaconess Cancer Center and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Nature
|August 22, 2008
Resumen
La exclusión del PTEN nuclear (el homólogo de la fosfatasa y la tensina eliminado en el cromosoma 10) conduce al cáncer. Una nueva red PML-DAXX-HAUSP controla la deubiquitinilación de PTEN y la entrada nuclear, ofreciendo información sobre la progresión del cáncer.
Área de la Ciencia:
- Oncología Oncología.
- Biología Molecular Biología Molecular
- Biología celular Biología celular.
Sus antecedentes:
- La exclusión nuclear del supresor tumoral PTEN se correlaciona con la progresión del cáncer.
- Los mecanismos que rigen la localización aberrante de PTEN en los cánceres humanos siguen sin estar claros.
- La ubicuidad de PTEN regula su partición nuclear-citoplasmática.
Objetivo del estudio:
- Para dilucidar los mecanismos que controlan la localización subcelular de PTEN en los cánceres humanos.
- Para identificar nuevos reguladores de la desbiquitinación de PTEN y el tráfico nuclear.
- Investigar el papel de la red PML-DAXX-HAUSP en la compartimentación de PTEN y el cáncer.
Principales métodos:
- Se investigó la localización de PTEN en relación con los cuerpos nucleares de la proteína de la leucemia mielótica (PML) y la proteasa específica de la ubiquitina asociada al herpesvirus (HAUSP/USP7).
- Utilizó tratamientos farmacológicos dirigidos a la degradación de PML-RARalpha (ácido retinoico todo-trans, trióxido de arsénico) para evaluar los efectos sobre el PTEN nuclear.
- Examinó la interacción entre PML, DAXX y HAUSP en el control de la desubiquitinación y el tráfico de PTEN.
- Se evaluó la expresión de HAUSP y la localización de PTEN en muestras de cáncer de próstata humano.
Principales resultados:
- Los organismos nucleares funcionales de PML se oponen a la actividad de HAUSP hacia PTEN, manteniendo la entrada nuclear de PTEN.
- El PTEN está localizado de manera aberrante en la leucemia mielótica aguda debido a la alteración de la función de la LMP.
- Tratamientos que degradan la PML-RARalpha restauró la localización nuclear del PTEN.
- PML se opone a la actividad de HAUSP a través de la proteína adaptadora DAXX.
- HAUSP se sobreexpresa en el cáncer de próstata, lo que se correlaciona con la exclusión nuclear PTEN.
Conclusiones:
- Una nueva red molecular PML-DAXX-HAUSP regula la desubiquitinación y el tráfico de PTEN.
- La perturbación de esta red por factores oncogénicos contribuye a la exclusión nuclear PTEN en el cáncer.
- Este estudio define un nuevo modelo dependiente de la deubiquitinación para la compartimentación subcelular de PTEN.
- Dirigirse a esta red puede ofrecer estrategias terapéuticas para los cánceres con localización PTEN aberrante.
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