Mono- Versus Polyubiquitination: Differential Control of p53 Fate by Mdm2

Muyang Li, Christopher L. Brooks, Foon Wu-Baer, Delin Chen, Richard Baer, Wei Gu^*

Abstract: Although Mdm2-mediated ubiquitination is essential for both degradation and nuclear export of p53, the molecular basis for the differential effects of Mdm2 remains unknown. Here we show that low levels of Mdm2 activity induce monoubiquitination and nuclear export of p53, whereas high levels promote p53's polyubiquitination and nuclear degradation. A p53-ubiquitin fusion protein that mimics monoubiquitinated p53 was found to accumulate in the cytoplasm in an Mdm2-independent manner, indicating that monoubiquitination is critical for p53 trafficking. These results clarify the nature of ubiquitination-mediated p53 regulation and suggest that distinct mechanisms regulate p53 function in accordance with the levels of Mdm2 activity.

Institute for Cancer Genetics and Department of Pathology, College of Physicians & Surgeons, Columbia University, 1150 St. Nicholas Avenue, New York, NY 10032, USA.

^* To whom correspondence should be addressed. E-mail: wg8{at}columbia.edu

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 |  Abstract »  |  Full Text »  |  PDF »

Regulation of p53 Localization and Activity by Ubc13.

A. Laine, I. Topisirovic, D. Zhai, J. C. Reed, K. L. B. Borden, and Z. Ronai (2006)
Mol. Cell. Biol. 26, 8901-8913
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MDM2 Is Required for Suppression of Apoptosis by Activated Akt1 in Salivary Acinar Cells.

K. H. Limesand, K. L. Schwertfeger, and S. M. Anderson (2006)
Mol. Cell. Biol. 26, 8840-8856
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p53-Independent Induction of Rat Hepatic Mdm2 following Administration of Phenobarbital and Pregnenolone 16{alpha}-Carbonitrile.

D. M. Nelson, V. Bhaskaran, W. R. Foster, and L. D. Lehman-McKeeman (2006)
Toxicol. Sci. 94, 272-280
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Posttranslational Modification and Cell Type-Specific Degradation of Varicella-Zoster Virus ORF29p.

C. L. Stallings and S. J. Silverstein (2006)
J. Virol. 80, 10836-10846
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Genetic and Expression Aberrations of E3 Ubiquitin Ligases in Human Breast Cancer.

C. Chen, A. K. Seth, and A. E. Aplin (2006)
Mol. Cancer Res. 4, 695-707
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Jab1 Induces the Cytoplasmic Localization and Degradation of p53 in Coordination with Hdm2.

W. Oh, E.-W. Lee, Y. H. Sung, M.-R. Yang, J. Ghim, H.-W. Lee, and J. Song (2006)
J. Biol. Chem. 281, 17457-17465
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Cell-Type-Specific Regulation of Degradation of Hypoxia-Inducible Factor 1{alpha}: Role of Subcellular Compartmentalization.

X. Zheng, J. L. Ruas, R. Cao, F. A. Salomons, Y. Cao, L. Poellinger, and T. Pereira (2006)
Mol. Cell. Biol. 26, 4628-4641
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Mechanisms for human cytomegalovirus-induced cytoplasmic p53 sequestration in endothelial cells.

B. Utama, Y. H. Shen, B. M. Mitchell, I. T. Makagiansar, Y. Gan, R. Muthuswamy, S. Duraisamy, D. Martin, X. Wang, M.-X. Zhang, et al. (2006)
J. Cell Sci. 119, 2457-2467
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The nuclear ubiquitin-proteasome system.

A. von Mikecz (2006)
J. Cell Sci. 119, 1977-1984
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White Spot Syndrome Virus Open Reading Frame 222 Encodes a Viral E3 Ligase and Mediates Degradation of a Host Tumor Suppressor via Ubiquitination.

F. He, B. J. Fenner, A. K. Godwin, and J. Kwang (2006)
J. Virol. 80, 3884-3892
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Ubiquitylation, phosphorylation and Orc2 modulate the subcellular location of Orc1 and prevent it from inducing apoptosis.

T. Saha, S. Ghosh, A. Vassilev, and M. L. DePamphilis (2006)
J. Cell Sci. 119, 1371-1382
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p19ras Interacts with and Activates p73 by Involving the MDM2 Protein.

M.-H. Jeong, J. Bae, W.-H. Kim, S.-M. Yoo, J.-W. Kim, P. I. Song, and K.-H. Choi (2006)
J. Biol. Chem. 281, 8707-8715
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Osteoblast differentiation and skeletal development are regulated by Mdm2-p53 signaling..

C. J. Lengner, H. A. Steinman, J. Gagnon, T. W. Smith, J. E. Henderson, B. E. Kream, G. S. Stein, J. B. Lian, and S. N. Jones (2006)
J. Cell Biol. 172, 909-921
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Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo.

S. Francoz, P. Froment, S. Bogaerts, S. De Clercq, M. Maetens, G. Doumont, E. Bellefroid, and J.-C. Marine (2006)
PNAS 103, 3232-3237
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Molecular Linkage Between the Kinase ATM and NF-{kappa}B Signaling in Response to Genotoxic Stimuli..

Z.-H. Wu, Y. Shi, R. S. Tibbetts, and S. Miyamoto (2006)
Science 311, 1141-1146
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The Cellular Localization Pattern of Varicella-Zoster Virus ORF29p Is Influenced by Proteasome-Mediated Degradation.

C. L. Stallings, G. J. Duigou, A. A. Gershon, M. D. Gershon, and S. J. Silverstein (2006)
J. Virol. 80, 1497-1512
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Charge Modification at Multiple C-terminal Lysine Residues Regulates p53 Oligomerization and Its Nucleus-Cytoplasm Trafficking.

Y. Kawaguchi, A. Ito, E. Appella, and T.-P. Yao (2006)
J. Biol. Chem. 281, 1394-1400
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A New I{kappa}B Kinase {beta} Inhibitor Prevents Human Breast Cancer Progression through Negative Regulation of Cell Cycle Transition.

A. Tanaka, S. Muto, M. Konno, A. Itai, and H. Matsuda (2006)
Cancer Res. 66, 419-426
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Protein composition of the intranuclear inclusions of FXTAS.

C. K. Iwahashi, D. H. Yasui, H.-J. An, C. M. Greco, F. Tassone, K. Nannen, B. Babineau, C. B. Lebrilla, R. J. Hagerman, and P. J. Hagerman (2006)
Brain 129, 256-271
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Ubiquitination of p53 at Multiple Sites in the DNA-Binding Domain.

W. M. Chan, M. C. Mak, T. K. Fung, A. Lau, W. Y. Siu, and R. Y.C. Poon (2006)
Mol. Cancer Res. 4, 15-25
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