The Journal of Experimental Medicine
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Published 7 June 2004. doi:10.1084/jem.20031943
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 11, 1545-1557
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Ubiquitin-dependent Degradation of p73 Is Inhibited by PML

Francesca Bernassola1,2, Paolo Salomoni1,2, Andrew Oberst1,2,3, Charles J. Di Como2, Michele Pagano4, Gerry Melino3,5, and Pier Paolo Pandolfi1,2

1 Molecular Biology Program and 2 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
3 IDI-IRCCS Biochemistry Lab, Department of Experimental Medicine, University of Rome "Tor Vergata," 00139 Rome, Italy
4 Department of Pathology, New York University School of Medicine, New York, NY 10016
5 Toxicology Unit, Medical Research Council, University of Leicester, Leicester LE1 9HN, England, UK

Address correspondence to Pier Paolo Pandolfi, Molecular Biology Program and Dept. of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Phone: (212) 639-6168; Fax: (212) 717-3102; email: p-pandolfi{at}ski.mskcc.org

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.

Key Words: ubiquitinylation • acetylation • nuclear body • transcription • apoptosis

The online version of this article contains supplemental material.

The present address of F. Bernassola is IDI-IRCCS Biochemistry Lab, Department of Experimental Medicine, University of Rome "Tor Vergata," 00139 Rome, Italy.

The present address of P. Salomoni is Toxicology Unit, Medical Research Council, Toxicology Unit, University of Leicester, Leicester LE1 9HN, England, UK.

The present address of C.J. Di Como is Aureon Biosciences Corporation, Yonkers, NY 10701.

Abbreviations used in this paper: APL, acute promyelocytic leukemia; CHX, cycloheximide; DAPI, 4',6-diamidino-2-phenylindole; HAT, histone acetyltransferase; HA-Ub, HA-tagged ubiquitin; MAPK, mitogen-activated protein kinase; MEF, mouse embryonic fibroblast; NB, nuclear body; PML, promyelocytic leukemia; RAR{alpha}, retinoic acid receptor.


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