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JAK2 fosforila la histona H3Y41 y excluye HP1alpha de la cromatina

Mark A Dawson¹, Andrew J Bannister, Berthold Göttgens

¹Cambridge Institute for Medical Research and Department of Haematology, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK.

|September 29, 2009

Resumen

La Janus quinasa 2 (JAK2) fosforila la histona H3 en el núcleo, afectando la expresión génica. Este descubrimiento revela un vínculo directo entre JAK2 y el oncogén lmo2 en la leucemia.

Área de la Ciencia:

Biología Molecular Biología Molecular
Biología celular Biología celular.
Biología del cáncer Biología del cáncer.

Sus antecedentes:

La activación de Janus kinase 2 (JAK2) es común en las malignidades hematológicas.
JAK2 es una tirosina quinasa no receptor que regula los procesos celulares a través de la señalización citoplasmática.

Objetivo del estudio:

Para investigar el papel nuclear de JAK2.2.
Para identificar nuevos sustratos y socios de unión de JAK2 en el núcleo.
Para dilucidar el mecanismo que vincula JAK2 a la expresión oncogénica en la leucemia.

Principales métodos:

Inmunoprecipitación y Western blotting para detectar las interacciones y modificaciones de las proteínas.
Inmunoprecipitación de cromatina (ChIP) para evaluar la unión a las proteínas en los promotores de genes.
Ensayos de inhibición de JAK2 en células leucémicas humanas.

Principales resultados:

Se encontró JAK2 humano en el núcleo de las células hematopoyéticas.
JAK2 fosforila directamente la tirosina 41 (Y41) en la histona H3.3 y también en la tirosina.
La fosforilación de H3Y41 por JAK2 inhibe la unión de la proteína 1alfa de la heterocromatina (HP1alfa).
La inhibición de JAK2 disminuyó la expresión de lmo2 y la fosforilación de H3Y41 en el promotor de lmo2, aumentando la unión de HP1alfa.

Conclusiones:

JAK2 tiene una función nuclear no reconocida anteriormente en la fosforilación de H3Y41.1.
Este evento de fosforilación crea un vínculo mecánico entre JAK2 y el oncogén hematopoyético lmo2.
La vía JAK2-H3Y41-HP1alpha está implicada en la regulación de los genes involucrados en la hematopoyesis y la leucemia.

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