PML regulates p53 stability by sequestering Mdm2 to the nucleolus.
Nat Cell Biol
; 6(7): 665-72, 2004 Jul.
Article
en En
| MEDLINE
| ID: mdl-15195100
ABSTRACT
The promyelocytic leukaemia (PML) tumour-suppressor protein potentiates p53 function by regulating post-translational modifications, such as CBP-dependent acetylation and Chk2-dependent phosphorylation, in the PML-Nuclear Body (NB). PML was recently shown to interact with the p53 ubiquitin-ligase Mdm2 (refs 4-6); however, the mechanism by which PML regulates Mdm2 remains unclear. Here, we show that PML enhances p53 stability by sequestering Mdm2 to the nucleolus. We found that after DNA damage, PML and Mdm2 accumulate in the nucleolus in an Arf-independent manner. In addition, we found that the nucleolar localization of PML is dependent on ATR activation and phosphorylation of PML by ATR. Notably, in Pml(-/-) cells, sequestration of Mdm2 to the nucleolus was impaired, as well as p53 stabilization and the induction of apoptosis. Furthermore, we demonstrate that PML physically associates with the nucleolar protein L11, and that L11 knockdown impairs the ability of PML to localize to nucleoli after DNA damage. These findings demonstrate an unexpected role of PML in the nucleolar network for tumour suppression.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
/
Proteínas Nucleares
/
Nucléolo Celular
/
Proteína p53 Supresora de Tumor
/
Proteínas Proto-Oncogénicas
/
Proteínas Supresoras de Tumor
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Proteínas de Neoplasias
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Cell Biol
Año:
2004
Tipo del documento:
Article
País de afiliación:
Estados Unidos