p73 has been identified recently as a structural and functional homologue of the tumor suppressor p53. Here, we report that p73 stability is directly regulated by the ubiquitin-proteasome pathway. Furthermore, we show that the promyelocytic leukemia (PML) protein modulates p73 half-life by inhibiting its degradation in a PML-nuclear body (NB)-dependent manner. p38 mitogen-activated protein kinase-mediated phosphorylation of p73 is required for p73 recruitment into the PML-NB and subsequent PML-dependent p73 stabilization. We find that p300-mediated acetylation of p73 protects it against ubiquitinylation and that PML regulates p73 stability by positively modulating its acetylation levels. As a result, PML potentiates p73 transcriptional and proapoptotic activities that are markedly impaired in Pml-/- primary cells. Our findings demonstrate that PML plays a crucial role in modulating p73 function, thus providing further insights on the molecular network for tumor suppression.

Ubiquitin-dependent degradation of p73 is inhibited by PML.

PANDOLFI DE RINALDIS, Pier Paolo
2004-01-01

Abstract

p73 has been identified recently as a structural and functional homologue of the tumor suppressor p53. Here, we report that p73 stability is directly regulated by the ubiquitin-proteasome pathway. Furthermore, we show that the promyelocytic leukemia (PML) protein modulates p73 half-life by inhibiting its degradation in a PML-nuclear body (NB)-dependent manner. p38 mitogen-activated protein kinase-mediated phosphorylation of p73 is required for p73 recruitment into the PML-NB and subsequent PML-dependent p73 stabilization. We find that p300-mediated acetylation of p73 protects it against ubiquitinylation and that PML regulates p73 stability by positively modulating its acetylation levels. As a result, PML potentiates p73 transcriptional and proapoptotic activities that are markedly impaired in Pml-/- primary cells. Our findings demonstrate that PML plays a crucial role in modulating p73 function, thus providing further insights on the molecular network for tumor suppression.
2004
199
1545
1557
http://dx.doi.org/10.1084/jem.20031943
Acetylation; Cells; Cultured; DNA-Binding Proteins; Genes; Tumor Suppressor; Humans; Mitogen-Activated Protein Kinases; Neoplasm Proteins; Nuclear Proteins; Receptors; Retinoic Acid; Trans-Activators; Transcription Factors; Tumor Suppressor Proteins; Ubiquitin; p38 Mitogen-Activated Protein Kinases
F. Bernassola;P. Salomoni;A. Oberst;C. J. Di Como;M. Pagano;G. Melino;P. P. Pandolfi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/60919
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