PML regulates p53 stability by sequestering Mdm2 to the nucleolus

Rosa Bernardi, Pier Paolo Scaglioni, Stephan Bergmann, Henning Horn, Karen H. Vousden, Pier Paolo Pandolfi

Research output: Contribution to journalArticle

249 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)665-672
Number of pages8
JournalNature Cell Biology
Volume6
Issue number7
DOIs
Publication statusPublished - Jul 2004
Externally publishedYes

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Leukemia
DNA Damage
Phosphorylation
Tumor Suppressor Protein p53
Post Translational Protein Processing
Ligases
Nuclear Proteins
Ubiquitin
Apoptosis
Neoplasms

ASJC Scopus subject areas

  • Cell Biology

Cite this

Bernardi, R., Scaglioni, P. P., Bergmann, S., Horn, H., Vousden, K. H., & Pandolfi, P. P. (2004). PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nature Cell Biology, 6(7), 665-672. https://doi.org/10.1038/ncb1147

PML regulates p53 stability by sequestering Mdm2 to the nucleolus. / Bernardi, Rosa; Scaglioni, Pier Paolo; Bergmann, Stephan; Horn, Henning; Vousden, Karen H.; Pandolfi, Pier Paolo.

In: Nature Cell Biology, Vol. 6, No. 7, 07.2004, p. 665-672.

Research output: Contribution to journalArticle

Bernardi, R, Scaglioni, PP, Bergmann, S, Horn, H, Vousden, KH & Pandolfi, PP 2004, 'PML regulates p53 stability by sequestering Mdm2 to the nucleolus', Nature Cell Biology, vol. 6, no. 7, pp. 665-672. https://doi.org/10.1038/ncb1147
Bernardi R, Scaglioni PP, Bergmann S, Horn H, Vousden KH, Pandolfi PP. PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nature Cell Biology. 2004 Jul;6(7):665-672. https://doi.org/10.1038/ncb1147
Bernardi, Rosa ; Scaglioni, Pier Paolo ; Bergmann, Stephan ; Horn, Henning ; Vousden, Karen H. ; Pandolfi, Pier Paolo. / PML regulates p53 stability by sequestering Mdm2 to the nucleolus. In: Nature Cell Biology. 2004 ; Vol. 6, No. 7. pp. 665-672.
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