Ubiquitin-dependent degradation of p73 is inhibited by PML.
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.
Bernassola
Francesca
F
Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA.
Salomoni
Paolo
P
Oberst
Andrew
A
Di Como
Charles J
CJ
Pagano
Michele
M
Melino
Gerry
G
Pandolfi
Pier Paolo
PP
D000107:Acetylation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009363:Neoplasm Proteins / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism* / Q000502:physiology*; D000071156:Promyelocytic Leukemia Protein; D018168:Receptors, Retinoic Acid / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C000606460:TP73 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C070576:PML protein, human; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases