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Science 300 (5617): 342-344

Copyright © 2003 by the American Association for the Advancement of Science

Polyubiquitination of p53 by a Ubiquitin Ligase Activity of p300

Steven R. Grossman,124* Maria E. Deato,1dagger Chrystelle Brignone,1* Ho Man Chan,1 Andrew L. Kung,135 Hideaki Tagami,1 Yoshihiro Nakatani,16 David M. Livingston147ddagger

Rapid turnover of the tumor suppressor protein p53 requires the MDM2 ubiquitin ligase, and both interact with p300-CREB-binding protein transcriptional coactivator proteins. p53 is stabilized by the binding of p300 to the oncoprotein E1A, suggesting that p300 regulates p53 degradation. Purified p300 exhibited intrinsic ubiquitin ligase activity that was inhibited by E1A. In vitro, p300 with MDM2 catalyzed p53 polyubiquitination, whereas MDM2 catalyzed p53 monoubiquitination. E1A expression caused a decrease in polyubiquitinated but not monoubiquitinated p53 in cells. Thus, generation of the polyubiquitinated forms of p53 that are targeted for proteasome degradation requires the intrinsic ubiquitin ligase activities of MDM2 and p300.

1 Department of Cancer Biology,
2 Department of Adult Oncology,
3 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
4 Department of Medicine,
5 Department of Pediatrics,
6 Department of Biological Chemistry and Molecular Pharmacology,
7 Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
*   Present address: Department of Cancer Biology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.

dagger    Present address: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.

ddagger    To whom correspondence should be addressed. E-mail: david_livingston{at}

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MDM2 Mediates p300/CREB-binding Protein-associated Factor Ubiquitination and Degradation.
Y. Jin, S. X. Zeng, H. Lee, and H. Lu (2004)
J. Biol. Chem. 279, 20035-20043
   Abstract »    Full Text »    PDF »
TSG101 Interacts with Apoptosis-antagonizing Transcription Factor and Enhances Androgen Receptor-mediated Transcription by Promoting Its Monoubiquitination.
S. Burgdorf, P. Leister, and K. H. Scheidtmann (2004)
J. Biol. Chem. 279, 17524-17534
   Abstract »    Full Text »    PDF »
Control of Human PIRH2 Protein Stability: INVOLVEMENT OF TIP60 AND THE PROTEASOME.
I. R. Logan, V. Sapountzi, L. Gaughan, D. E. Neal, and C. N. Robson (2004)
J. Biol. Chem. 279, 11696-11704
   Abstract »    Full Text »    PDF »
Participation of the Ubiquitin-Conjugating Enzyme UBE2E3 in Nedd4-2-Dependent Regulation of the Epithelial Na+ Channel.
C. Debonneville and O. Staub (2004)
Mol. Cell. Biol. 24, 2397-2409
   Abstract »    Full Text »    PDF »
Regulation of p53 Stability and Function in HCT116 Colon Cancer Cells.
M. D. Kaeser, S. Pebernard, and R. D. Iggo (2004)
J. Biol. Chem. 279, 7598-7605
   Abstract »    Full Text »    PDF »
Mdm2 in the Response to Radiation.
M. E. Perry (2004)
Mol. Cancer Res. 2, 9-19
   Abstract »    Full Text »    PDF »
The Co-repressor Hairless Protects ROR{alpha} Orphan Nuclear Receptor from Proteasome-mediated Degradation.
A. N. Moraitis and V. Giguere (2003)
J. Biol. Chem. 278, 52511-52518
   Abstract »    Full Text »    PDF »
Defective p53 Post-translational Modification Required for Wild Type p53 Inactivation in Malignant Epithelial Cells with mdm2 Gene Amplification.
C. D. Knights, Y. Liu, E. Appella, and M. Kulesz-Martin (2003)
J. Biol. Chem. 278, 52890-52900
   Abstract »    Full Text »    PDF »
Involvement of the DNA Repair Protein hHR23 in p53 Degradation.
S. Glockzin, F.-X. Ogi, A. Hengstermann, M. Scheffner, and C. Blattner (2003)
Mol. Cell. Biol. 23, 8960-8969
   Abstract »    Full Text »    PDF »
Mono- Versus Polyubiquitination: Differential Control of p53 Fate by Mdm2.
M. Li, C. L. Brooks, F. Wu-Baer, D. Chen, R. Baer, and W. Gu (2003)
Science 302, 1972-1975
   Abstract »    Full Text »    PDF »
The Proline Repeat Domain of p53 Binds Directly to the Transcriptional Coactivator p300 and Allosterically Controls DNA-Dependent Acetylation of p53.
D. Dornan, H. Shimizu, L. Burch, A. J. Smith, and T. R. Hupp (2003)
Mol. Cell. Biol. 23, 8846-8861
   Abstract »    Full Text »    PDF »
Ribosomal Protein L11 Negatively Regulates Oncoprotein MDM2 and Mediates a p53-Dependent Ribosomal-Stress Checkpoint Pathway.
Y. Zhang, G. W. Wolf, K. Bhat, A. Jin, T. Allio, W. A. Burkhart, and Y. Xiong (2003)
Mol. Cell. Biol. 23, 8902-8912
   Abstract »    Full Text »    PDF »
MDM2, An Introduction.
T. Iwakuma and G. Lozano (2003)
Mol. Cancer Res. 1, 993-1000
   Abstract »    Full Text »    PDF »
The MDM2-p53 Interaction.
U. M. Moll and O. Petrenko (2003)
Mol. Cancer Res. 1, 1001-1008
   Abstract »    Full Text »    PDF »
Cell Cycle Regulatory Functions of the Human Oncoprotein MDM2.
S. P. Deb (2003)
Mol. Cancer Res. 1, 1009-1016
   Abstract »    Full Text »    PDF »

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