期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 199, 期 11, 页码 1545-1557出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20031943
关键词
ubiquitinylation; acetylation; nuclear body; transcription; apoptosis
资金
- MRC [MC_U132670601] Funding Source: UKRI
- Medical Research Council [MC_U132670601] Funding Source: researchfish
- Medical Research Council [MC_U132670601] Funding Source: Medline
- NCI NIH HHS [R01-CA76584, CA-71692, R01 CA071692, R37 CA071692, R01 CA076584] Funding Source: Medline
- NIGMS NIH HHS [R01 GM057587, R01-GM57587] Funding Source: Medline
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.
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