PML regulates p53 stability by sequestering Mdm2 to the nucleolus Journal Article
| Authors: | Bernardi, R.; Scaglioni, P. P.; Bergmann, S.; Horn, H. F.; Vousden, K. H.; Pandolfi, P. P. |
| Article Title: | PML regulates p53 stability by sequestering Mdm2 to the nucleolus |
| 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. |
| Keywords: | controlled study; protein phosphorylation; unclassified drug; human cell; proto-oncogene proteins; protein localization; animals; cell cycle proteins; mice; dna damage; cells, cultured; apoptosis; nuclear protein; neoplasm proteins; protein stability; phosphorylation; protein p53; transcription factors; nuclear proteins; cancer inhibition; tumor suppressor gene; regulatory mechanism; protein-serine-threonine kinases; tumor suppressor proteins; protein transport; fibroblasts; cell line, transformed; tumor suppressor protein p53; cellular distribution; active transport, cell nucleus; rna stability; arf protein; tumor suppressor protein; nuclear localization signal; atr protein; nih 3t3 cells; ribosomal proteins; protein mdm2; proto-oncogene proteins c-mdm2; nucleolus; promyelocytic leukemia protein; cell dna; cell nucleolus; s phase kinase associated protein; adp-ribosylation factor 1; humans; human; priority journal; article; protein l 11; cell compartmentation |
| Journal Title: | Nature Cell Biology |
| Volume: | 6 |
| Issue: | 7 |
| ISSN: | 1465-7392 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2004-07-01 |
| Start Page: | 665 |
| End Page: | 672 |
| Language: | English |
| DOI: | 10.1038/ncb1147 |
| PROVIDER: | scopus |
| PUBMED: | 15195100 |
| DOI/URL: | |
| Notes: | Nature Cell Biol. -- Cited By (since 1996):189 -- Export Date: 16 June 2014 -- CODEN: NCBIF -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work