Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Mol. Cell. Biol. 21 (24): 8521-8532

Copyright © 2001 by the American Society for Microbiology. All rights reserved.

Molecular and Cellular Biology, December 2001, p. 8521-8532, Vol. 21, No. 24
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.24.8521-8532.2001

C-Terminal Ubiquitination of p53 Contributes to Nuclear Export

Marion A. E. Lohrum, Douglas B. Woods, Robert L. Ludwig, Éva Bálint, and Karen H. Vousden*

Regulation of Cell Growth Laboratory, National Cancer Institute at Frederick, Frederick, Maryland 21702-1201

Received Recieved 4 June 2001/Returned for modification 9 August 2001/Accepted 27 September 2001

The growth inhibitory functions of p53 are controlled in unstressed cells by rapid degradation of the p53 protein. One of the principal regulators of p53 stability is MDM2, a RING finger protein that functions as an E3 ligase to ubiquitinate p53. MDM2 promotes p53 nuclear export, and in this study, we show that ubiquitination of the C terminus of p53 by MDM2 contributes to the efficient export of p53 from the nucleus to the cytoplasm. In contrast, MDM2 did not promote nuclear export of the p53-related protein, p73. p53 nuclear export was enhanced by overexpression of the export receptor CRM1, although no significant relocalization of MDM2 was seen in response to CRM1. However, nuclear export driven by CRM1 overexpression did not result in the degradation of p53, and nuclear export was not essential for p53 degradation. These results indicate that MDM2 mediated ubiquitination of p53 contributes to both nuclear export and degradation of p53 but that these activities are not absolutely dependent on each other.


* Corresponding author. Mailing address: Regulation of Cell Growth Laboratory, NCI at Frederick, Building 560, Room 22-96, 1050 Boyles St., Frederick, MD 21702-1201. Phone: (301) 846-1726. Fax: (301) 846-1666. E-mail: vousden{at}ncifcrf.gov.


Molecular and Cellular Biology, December 2001, p. 8521-8532, Vol. 21, No. 24
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.24.8521-8532.2001

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Implicating SCF Complexes in Organogenesis in Caenorhabditis elegans.
S. R. G. Polley, A. Kuzmanov, J. Kuang, J. Karpel, V. Lazetic, E. I. Karina, B. L. Veo, and D. S. Fay (2014)
Genetics 196, 211-223
   Abstract »    Full Text »    PDF »
Acute exercise induces tumour suppressor protein p53 translocation to the mitochondria and promotes a p53-Tfam-mitochondrial DNA complex in skeletal muscle.
A. Saleem and D. A. Hood (2013)
J. Physiol. 591, 3625-3636
   Abstract »    Full Text »    PDF »
Expression and Role of p53 in the Retina.
L. Vuong, S. M. Conley, and M. R. Al-Ubaidi (2012)
Invest. Ophthalmol. Vis. Sci. 53, 1362-1371
   Abstract »    Full Text »    PDF »
Mdm2 and MdmX as Regulators of Gene Expression.
L. Biderman, J. L. Manley, and C. Prives (2012)
Genes & Cancer 3, 264-273
   Abstract »    Full Text »    PDF »
E3 Ligases Determine Ubiquitination Site and Conjugate Type by Enforcing Specificity on E2 Enzymes.
Y. David, N. Ternette, M. J. Edelmann, T. Ziv, B. Gayer, R. Sertchook, Y. Dadon, B. M. Kessler, and A. Navon (2011)
J. Biol. Chem. 286, 44104-44115
   Abstract »    Full Text »    PDF »
The Cancer-associated K351N Mutation Affects the Ubiquitination and the Translocation to Mitochondria of p53 Protein.
M. Muscolini, E. Montagni, V. Palermo, S. Di Agostino, W. Gu, S. Abdelmoula-Souissi, C. Mazzoni, G. Blandino, and L. Tuosto (2011)
J. Biol. Chem. 286, 39693-39702
   Abstract »    Full Text »    PDF »
Structural and Functional Comparison of the RING Domains of Two p53 E3 Ligases, Mdm2 and Pirh2.
J. Shloush, J. E. Vlassov, I. Engson, S. Duan, V. Saridakis, S. Dhe-paganon, B. Raught, Y. Sheng, and C. H. Arrowsmith (2011)
J. Biol. Chem. 286, 4796-4808
   Abstract »    Full Text »    PDF »
REG{gamma} modulates p53 activity by regulating its cellular localization.
J. Liu, G. Yu, Y. Zhao, D. Zhao, Y. Wang, L. Wang, J. Liu, L. Li, Y. Zeng, Y. Dang, et al. (2010)
J. Cell Sci. 123, 4076-4084
   Abstract »    Full Text »    PDF »
Apoptosis contributes to testicular toxicity induced by two isomers of bromopropanes.
Q.-Q. Xin, Yong Huang, Jie Li, W.-J. Zhang, Tao Yu, Hua Wang, Cheng Zhang, D.-Q. Ye, and Fen Huang (2010)
Toxicology and Industrial Health 26, 513-524
   Abstract »    PDF »
p53-based Cancer Therapy.
D. P. Lane, C. F. Cheok, and S. Lain (2010)
Cold Spring Harb Perspect Biol 2, a001222
   Abstract »    Full Text »    PDF »
Ubiquitin and Ubiquitin-Like Proteins in the Nucleolus: Multitasking Tools for a Ribosome Factory.
N. Shcherbik and D. G. Pestov (2010)
Genes & Cancer 1, 681-689
   Abstract »    Full Text »    PDF »
SHIP2 (SH2 Domain-containing Inositol Phosphatase 2) SH2 Domain Negatively Controls SHIP2 Monoubiquitination in Response to Epidermal Growth Factor.
J. De Schutter, A. Guillabert, V. Imbault, C. Degraef, C. Erneux, D. Communi, and I. Pirson (2009)
J. Biol. Chem. 284, 36062-36076
   Abstract »    Full Text »    PDF »
MSL2 Promotes Mdm2-independent Cytoplasmic Localization of p53.
J.-P. Kruse and W. Gu (2009)
J. Biol. Chem. 284, 3250-3263
   Abstract »    Full Text »    PDF »
p53 is localized to a sub-nucleolar compartment after proteasomal inhibition in an energy-dependent manner.
O. Karni-Schmidt, A. Zupnick, M. Castillo, A. Ahmed, T. Matos, P. Bouvet, C. Cordon-Cardo, and C. Prives (2008)
J. Cell Sci. 121, 4098-4105
   Abstract »    Full Text »    PDF »
TRAF6 and the Three C-Terminal Lysine Sites on IRF7 Are Required for Its Ubiquitination-Mediated Activation by the Tumor Necrosis Factor Receptor Family Member Latent Membrane Protein 1.
S. Ning, A. D. Campos, B. G. Darnay, G. L. Bentz, and J. S. Pagano (2008)
Mol. Cell. Biol. 28, 6536-6546
   Abstract »    Full Text »    PDF »
CRM1-mediated Nuclear Export Is Required for 26 S Proteasome-dependent Degradation of the TRIP-Br2 Proto-oncoprotein.
J. K. Cheong, L. Gunaratnam, and S. I-H. Hsu (2008)
J. Biol. Chem. 283, 11661-11676
   Abstract »    Full Text »    PDF »
Ubiquitination and Degradation of Mutant p53.
N. Lukashchuk and K. H. Vousden (2007)
Mol. Cell. Biol. 27, 8284-8295
   Abstract »    Full Text »    PDF »
Mechanistic Studies of MDM2-mediated Ubiquitination in p53 Regulation.
C. L. Brooks, M. Li, and W. Gu (2007)
J. Biol. Chem. 282, 22804-22815
   Abstract »    Full Text »    PDF »
Regulation of p53 Nuclear Export through Sequential Changes in Conformation and Ubiquitination.
L. Nie, M. Sasaki, and C. G. Maki (2007)
J. Biol. Chem. 282, 14616-14625
   Abstract »    Full Text »    PDF »
Nitric oxide controls nuclear export of APE1/Ref-1 through S-nitrosation of Cysteines 93 and 310.
J. Qu, G.-H. Liu, B. Huang, and C. Chen (2007)
Nucleic Acids Res. 35, 2522-2532
   Abstract »    Full Text »    PDF »
Stra13 is induced by genotoxic stress and regulates ionizing-radiation-induced apoptosis.
T. H. Thin, L. Li, T.-K. Chung, H. Sun, and R. Taneja (2007)
EMBO Rep. 8, 401-407
   Abstract »    Full Text »    PDF »
An Essential Role of Human Ada3 in p53 Acetylation.
A. Nag, A. Germaniuk-Kurowska, M. Dimri, M. A. Sassack, C. B. Gurumurthy, Q. Gao, G. Dimri, H. Band, and V. Band (2007)
J. Biol. Chem. 282, 8812-8820
   Abstract »    Full Text »    PDF »
The p53 Isoform {Delta}p53 Lacks Intrinsic Transcriptional Activity and Reveals the Critical Role of Nuclear Import in Dominant-Negative Activity.
W. M. Chan and R. Y.C. Poon (2007)
Cancer Res. 67, 1959-1969
   Abstract »    Full Text »    PDF »
Mdm2 targets the p53 transcription cofactor JMY for degradation.
A. S. Coutts, H. Boulahbel, A. Graham, and N. B. La Thangue (2007)
EMBO Rep. 8, 84-90
   Abstract »    Full Text »    PDF »
Mdm2-mediated NEDD8 Modification of TAp73 Regulates Its Transactivation Function.
I. R. Watson, A. Blanch, D. C. C. Lin, M. Ohh, and M. S. Irwin (2006)
J. Biol. Chem. 281, 34096-34103
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Genotoxic Stress and Cellular Stress Alter the Subcellular Distribution of Human T-Cell Leukemia Virus Type 1 Tax through a CRM1-Dependent Mechanism.
M. L. Gatza and S. J. Marriott (2006)
J. Virol. 80, 6657-6668
   Abstract »    Full Text »    PDF »
Platelet-Derived Growth Factor BB Induces Nuclear Export and Proteasomal Degradation of CREB via Phosphatidylinositol 3-Kinase/Akt Signaling in Pulmonary Artery Smooth Muscle Cells.
C. V. Garat, D. Fankell, P. F. Erickson, J. E.-B. Reusch, N. N. Bauer, I. F. McMurtry, and D. J. Klemm (2006)
Mol. Cell. Biol. 26, 4934-4948
   Abstract »    Full Text »    PDF »
Excess HDM2 Impacts Cell Cycle and Apoptosis and Has a Selective Effect on p53-dependent Transcription.
S. Ohkubo, T. Tanaka, Y. Taya, K. Kitazato, and C. Prives (2006)
J. Biol. Chem. 281, 16943-16950
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Regulation of transactivation-independent proapoptotic activity of p53 by FOXO3a.
H. You, K. Yamamoto, and T. W. Mak (2006)
PNAS 103, 9051-9056
   Abstract »    Full Text »    PDF »
Inhibition of the ATM/p53 Signal Transduction Pathway by Kaposi's Sarcoma-Associated Herpesvirus Interferon Regulatory Factor 1.
Y. C. Shin, H. Nakamura, X. Liang, P. Feng, H. Chang, T. F. Kowalik, and J. U. Jung (2006)
J. Virol. 80, 2257-2266
   Abstract »    Full Text »    PDF »
Camptothecin Induces Nuclear Export of Prohibitin Preferentially in Transformed Cells through a CRM-1-dependent Mechanism.
S. Rastogi, B. Joshi, G. Fusaro, and S. Chellappan (2006)
J. Biol. Chem. 281, 2951-2959
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Complicating the complexity of p53.
K. S. Yee and K. H. Vousden (2005)
Carcinogenesis 26, 1317-1322
   Abstract »    Full Text »    PDF »
Involvement of Nuclear Export in Human Papillomavirus Type 18 E6-Mediated Ubiquitination and Degradation of p53.
D. Stewart, A. Ghosh, and G. Matlashewski (2005)
J. Virol. 79, 8773-8783
   Abstract »    Full Text »    PDF »
Activating transcription factor 3, a stress sensor, activates p53 by blocking its ubiquitination.
C. Yan, D. Lu, T. Hai, and D. D. Boyd (2005)
EMBO J. 24, 2425-2435
   Abstract »    Full Text »    PDF »
A Serine/Threonine-rich Motif Is One of Three Nuclear Localization Signals That Determine Unidirectional Transport of the Mineralocorticoid Receptor to the Nucleus.
R. F. Walther, E. Atlas, A. Carrigan, Y. Rouleau, A. Edgecombe, L. Visentin, C. Lamprecht, G. C. Addicks, R. J. G. Hache, and Y. A. Lefebvre (2005)
J. Biol. Chem. 280, 17549-17561
   Abstract »    Full Text »    PDF »
A 10-Amino Acid Domain within Human T-cell Leukemia Virus Type 1 and Type 2 Tax Protein Sequences Is Responsible for Their Divergent Subcellular Distribution.
L. Meertens, S. Chevalier, R. Weil, A. Gessain, and R. Mahieux (2004)
J. Biol. Chem. 279, 43307-43320
   Abstract »    Full Text »    PDF »
Lysines Close to the Rous Sarcoma Virus Late Domain Critical for Budding.
J. L. Spidel, R. C. Craven, C. B. Wilson, A. Patnaik, H. Wang, L. M. Mansky, and J. W. Wills (2004)
J. Virol. 78, 10606-10616
   Abstract »    Full Text »    PDF »
Translocation of the inhibitor of apoptosis protein c-IAP1 from the nucleus to the Golgi in hematopoietic cells undergoing differentiation: a nuclear export signal-mediated event.
S. Plenchette, S. Cathelin, C. Rebe, S. Launay, S. Ladoire, O. Sordet, T. Ponnelle, N. Debili, T.-H. Phan, R.-A. Padua, et al. (2004)
Blood 104, 2035-2043
   Abstract »    Full Text »    PDF »
Ribosomal Protein L23 Activates p53 by Inhibiting MDM2 Function in Response to Ribosomal Perturbation but Not to Translation Inhibition.
M.-S. Dai, S. X. Zeng, Y. Jin, X.-X. Sun, L. David, and H. Lu (2004)
Mol. Cell. Biol. 24, 7654-7668
   Abstract »    Full Text »    PDF »
Proteasomal Degradation of the Nuclear Targeting Growth Factor Midkine.
N. Suzuki, Y. Shibata, T. Urano, T. Murohara, T. Muramatsu, and K. Kadomatsu (2004)
J. Biol. Chem. 279, 17785-17791
   Abstract »    Full Text »    PDF »
Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for p53 activation.
J. M. Stommel and G. M. Wahl (2004)
EMBO J. 23, 1547-1556
   Abstract »    Full Text »    PDF »
Impaired p53 Expression, Function, and Nuclear Localization in Calreticulin-deficient Cells.
N. Mesaeli and C. Phillipson (2004)
Mol. Biol. Cell 15, 1862-1870
   Abstract »    Full Text »    PDF »
hGTSE-1 Expression Stimulates Cytoplasmic Localization of p53.
M. Monte, R. Benetti, L. Collavin, L. Marchionni, G. Del Sal, and C. Schneider (2004)
J. Biol. Chem. 279, 11744-11752
   Abstract »    Full Text »    PDF »
Acetylation of p53 augments its site-specific DNA binding both in vitro and in vivo.
J. Luo, M. Li, Y. Tang, M. Laszkowska, R. G. Roeder, and W. Gu (2004)
PNAS 101, 2259-2264
   Abstract »    Full Text »    PDF »
Phosphorylation of Serine 18 Regulates Distinct p53 Functions in Mice.
H. K. Sluss, H. Armata, J. Gallant, and S. N. Jones (2004)
Mol. Cell. Biol. 24, 976-984
   Abstract »    Full Text »    PDF »
p53 Activation in Chronic Radiation-Treated Breast Cancer Cells: Regulation of MDM2/p14ARF.
L. Xia, A. Paik, and J. J. Li (2004)
Cancer Res. 64, 221-228
   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 MDM2-p53 Interaction.
U. M. Moll and O. Petrenko (2003)
Mol. Cancer Res. 1, 1001-1008
   Abstract »    Full Text »    PDF »
Nuclear and cytoplasmic degradation of endogenous p53 and HDM2 occurs during down-regulation of the p53 response after multiple types of DNA damage.
T. W. JOSEPH, A. ZAIKA, and U. M. MOLL (2003)
FASEB J 17, 1622-1630
   Abstract »    Full Text »    PDF »
Death Inducer-Obliterator 1 Triggers Apoptosis after Nuclear Translocation and Caspase Upregulation.
D. Garcia-Domingo, D. Ramirez, G. Gonzalez de Buitrago, and C. Martinez-A (2003)
Mol. Cell. Biol. 23, 3216-3225
   Abstract »    Full Text »    PDF »
Stabilization of p53 by CP-31398 Inhibits Ubiquitination without Altering Phosphorylation at Serine 15 or 20 or MDM2 Binding.
W. Wang, R. Takimoto, F. Rastinejad, and W. S. El-Deiry (2003)
Mol. Cell. Biol. 23, 2171-2181
   Abstract »    Full Text »    PDF »
Acetylation of p53 Inhibits Its Ubiquitination by Mdm2.
M. Li, J. Luo, C. L. Brooks, and W. Gu (2002)
J. Biol. Chem. 277, 50607-50611
   Abstract »    Full Text »    PDF »
Analysis of the Adenovirus E1B-55K-Anchored Proteome Reveals Its Link to Ubiquitination Machinery.
J. N. Harada, A. Shevchenko, A. Shevchenko, D. C. Pallas, and A. J. Berk (2002)
J. Virol. 76, 9194-9206
   Abstract »    Full Text »    PDF »
Identification of p53 Sequence Elements That Are Required for MDM2-Mediated Nuclear Export.
J. Gu, L. Nie, D. Wiederschain, and Z.-M. Yuan (2001)
Mol. Cell. Biol. 21, 8533-8546
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882