TY - JOUR
T1 - PML regulates p53 stability by sequestering Mdm2 to the nucleolus
AU - Bernardi, Rosa
AU - Scaglioni, Pier Paolo
AU - Bergmann, Stephan
AU - Horn, Henning F.
AU - Vousden, Karen H.
AU - Pandolfi, Pier Paolo
N1 - Funding Information:
We are indebted to I. Guernah, A. Guo, P. Salomoni, F. Bernassola, and S. Grisendi for suggestions during the course of this work and critical reading of the manuscript. We are grateful to W. Cliby, C. Di Como, W. Gu, A. Levine, S. Lowe, G. Lozano, C. Prives, S. Schreiber, M. Turker, M. van Lohuizen and A. Weismann for reagents and advice. We thank Y. Haupt for useful discussion. R.B. and P.P.S. were supported by T32 training grants from the National Institutes of Health. P.P.S. is also a recipient of an ASCO Young Investigator Award and a CALGB Oncology Fellows Award. This work was supported by the award of a National Institutes of Health grant RO1 CA-71692 to P.P.P.
PY - 2004/7
Y1 - 2004/7
N2 - The promyelocytic leukaemia (PML) tumour-suppressor protein potentiates p53 function by regulating post-translational modifications, such as CBP-dependent acetylation1,2 and Chk2-dependent phosphorylation, in the PML-Nuclear Body (NB)3. 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.
AB - The promyelocytic leukaemia (PML) tumour-suppressor protein potentiates p53 function by regulating post-translational modifications, such as CBP-dependent acetylation1,2 and Chk2-dependent phosphorylation, in the PML-Nuclear Body (NB)3. 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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U2 - 10.1038/ncb1147
DO - 10.1038/ncb1147
M3 - Article
C2 - 15195100
AN - SCOPUS:3242726103
SN - 1465-7392
VL - 6
SP - 665
EP - 672
JO - Nature cell biology
JF - Nature cell biology
IS - 7
ER -