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La IkappaB quinasa promueve la tumorigénesis a través de la inhibición de la horquilla FOXO3a

Mickey C-T Hu¹, Dung-Fang Lee, Weiya Xia

¹Department of Molecular and Cellular Oncology, The University of Texas, Houston, TX 77030, USA. michu@mdanderson.org

|April 16, 2004

Resumen

La exclusión nuclear de FOXO3a, normalmente regulada por Akt, también puede ocurrir de forma independiente a través de IKK. Esta vía mediada por IKK promueve la proliferación celular y la tumorigénesis, lo que afecta la supervivencia del cáncer de mama.

Área de la Ciencia:

Biología Molecular Biología Molecular
Investigación del cáncer Investigación del cáncer.
La señalización celular de las células.

Sus antecedentes:

El factor de transcripción FOXO3a es normalmente excluido del núcleo por Akt, promoviendo la supervivencia celular.
El entendimiento previo vinculaba la exclusión nuclear de FOXO3a únicamente a la fosforilación de Akt.

Objetivo del estudio:

Para investigar la relación patológica entre el fosforilado-Akt (Akt-p) y FOXO3a en tumores primarios.
Identificar mecanismos alternativos que regulen la localización de FOXO3a más allá de la señalización Akt.

Principales métodos:

Análisis de tumores primarios para evaluar la localización de Akt-p y FOXO3a.
Experimentos in vitro que demuestran la interacción de la IkappaB quinasa (IKK) con, la fosforilación de y la inhibición de FOXO3a.
Investigación de la proteólisis de FOXO3a a través de la vía del proteasoma dependiente de Ub.
Análisis de correlación del FOXO3a citoplasmático con la expresión IKKbeta o Akt-p.
Evaluación del efecto de IKKbeta en la proliferación celular y la tumorigénesis, y el papel de FOXO3a en este proceso.

Principales resultados:

Se encontró que FOXO3a estaba excluido del núcleo en algunos tumores que carecían de Akt-p, lo que indica un mecanismo independiente de Akt.
Se demostró que la IkappaB quinasa (IKK) interactúa físicamente con, fosforila y inhibe FOXO3a independientemente de Akt.
La inhibición mediada por IKK de FOXO3a conduce a su proteólisis a través de la vía del proteosoma dependiente de Ub.
El FOXO3a citoplasmático se correlaciona con la expresión de IKKbeta o Akt-p y se asocia con una pobre supervivencia en el cáncer de mama.
La expresión constitutiva de IKKbeta promueve la proliferación celular y la tumorigénesis, efectos que pueden ser contrarrestados por FOXO3a.

Conclusiones:

La IkappaB quinasa (IKK) representa una nueva vía para la regulación negativa de la localización y función de FOXO3a.
Esta localización citoplasmática mediada por IKK de FOXO3a es un mecanismo clave que promueve el crecimiento celular y la tumorigénesis.
Los hallazgos revelan un papel crítico para IKK en el desarrollo del cáncer, independiente de la bien establecida vía Akt.

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