This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, Y. Articles by Xiong, Y. Search for Related Content PubMed PubMed Citation Articles by Zhang, Y. Articles by Xiong, Y.

Control of p53 Ubiquitination and Nuclear Export by MDM2 and ARF¹

Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [Y. Z.], and Lineberger Comprehensive Cancer Center and Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295 [Y. X.]

p53 and ARF-INK4a are the two most frequently altered loci in human tumors. The activity of p53 protein is inhibited during normal cell growth by the proto-oncoprotein MDM2 through either repression of p53-mediated transcription in the nucleus or proteasomal degradation of p53 protein in the cytoplasm. Responding to oncogenic signal-activated cell hyperproliferation, ARF-mediated antagonism of MDM2 inhibition results in p53 becoming active and its protein levels rising. The biochemical mechanisms of ubiquitination and nuclear export that underlie the functions of ARF and MDM2 in p53 control continue to emerge.

This article has been cited by other articles:

				J.-P. Kruse and W. Gu MSL2 Promotes Mdm2-independent Cytoplasmic Localization of p53 J. Biol. Chem., January 30, 2009; 284(5): 3250 - 3263. [Abstract] [Full Text] [PDF]

				M.-S. Dai, X.-X. Sun, and H. Lu Aberrant Expression of Nucleostemin Activates p53 and Induces Cell Cycle Arrest via Inhibition of MDM2 Mol. Cell. Biol., July 1, 2008; 28(13): 4365 - 4376. [Abstract] [Full Text] [PDF]

				J. Montalbano, W. Jin, M. S. Sheikh, and Y. Huang RBEL1 Is a Novel Gene That Encodes a Nucleocytoplasmic Ras Superfamily GTP-binding Protein and Is Overexpressed in Breast Cancer J. Biol. Chem., December 28, 2007; 282(52): 37640 - 37649. [Abstract] [Full Text] [PDF]

				C. L. Brooks, M. Li, and W. Gu Mechanistic Studies of MDM2-mediated Ubiquitination in p53 Regulation J. Biol. Chem., August 3, 2007; 282(31): 22804 - 22815. [Abstract] [Full Text] [PDF]

				C. Gross, G. Buchwalter, H. Dubois-Pot, E. Cler, H. Zheng, and B. Wasylyk The Ternary Complex Factor Net Is Downregulated by Hypoxia and Regulates Hypoxia-Responsive Genes Mol. Cell. Biol., June 1, 2007; 27(11): 4133 - 4141. [Abstract] [Full Text] [PDF]

				M. S. Lindstrom, A. Jin, C. Deisenroth, G. White Wolf, and Y. Zhang Cancer-Associated Mutations in the MDM2 Zinc Finger Domain Disrupt Ribosomal Protein Interaction and Attenuate MDM2-Induced p53 Degradation Mol. Cell. Biol., February 1, 2007; 27(3): 1056 - 1068. [Abstract] [Full Text] [PDF]

				S. Ueda, K. Fukamachi, Y. Matsuoka, N. Takasuka, F. Takeshita, A. Naito, M. Iigo, D. B. Alexander, M. A. Moore, I. Saito, et al. Ductal origin of pancreatic adenocarcinomas induced by conditional activation of a human Ha-ras oncogene in rat pancreas Carcinogenesis, December 1, 2006; 27(12): 2497 - 2510. [Abstract] [Full Text] [PDF]

				W. Chien, D. Yin, D. Gui, A. Mori, J. M. Frank, J. Said, D. Kusuanco, A. Marchevsky, R. McKenna, and H. P. Koeffler Suppression of Cell Proliferation and Signaling Transduction by Connective Tissue Growth Factor in Non-Small Cell Lung Cancer Cells Mol. Cancer Res., August 1, 2006; 4(8): 591 - 598. [Abstract] [Full Text] [PDF]

				W. H. Faour, Q. He, A. Mancini, D. Jovanovic, J. Antoniou, and J. A. Di Battista Prostaglandin E2 Stimulates p53 Transactivational Activity through Specific Serine 15 Phosphorylation in Human Synovial Fibroblasts: ROLE IN SUPPRESSION OF c/EBP/NF-{kappa}B-MEDIATED MEKK1-INDUCED MMP-1 EXPRESSION J. Biol. Chem., July 21, 2006; 281(29): 19849 - 19860. [Abstract] [Full Text] [PDF]

				E. Colombo, P. Martinelli, R. Zamponi, D. C. Shing, P. Bonetti, L. Luzi, S. Volorio, L. Bernard, G. Pruneri, M. Alcalay, et al. Delocalization and Destabilization of the Arf Tumor Suppressor by the Leukemia-Associated NPM Mutant. Cancer Res., March 15, 2006; 66(6): 3044 - 3050. [Abstract] [Full Text] [PDF]

				Y. Xiong and Y. Kotake No exit strategy? No problem: APC inhibits beta-catenin inside the nucleus. Genes & Dev., March 15, 2006; 20(6): 637 - 642. [Full Text] [PDF]

				S. C. Kaul, S. Aida, T. Yaguchi, K. Kaur, and R. Wadhwa Activation of Wild Type p53 Function by Its Mortalin-binding, Cytoplasmically Localizing Carboxyl Terminus Peptides J. Biol. Chem., November 25, 2005; 280(47): 39373 - 39379. [Abstract] [Full Text] [PDF]

				A. Datta, J. Sen, J. Hagen, C. K. Korgaonkar, M. Caffrey, D. E. Quelle, D. E. Hughes, T. J. Ackerson, R. H. Costa, and P. Raychaudhuri ARF Directly Binds DP1: Interaction with DP1 Coincides with the G1 Arrest Function of ARF Mol. Cell. Biol., September 15, 2005; 25(18): 8024 - 8036. [Abstract] [Full Text] [PDF]

				L. Chen, C. Li, Y. Pan, and J. Chen Regulation of p53-MDMX Interaction by Casein Kinase 1 Alpha Mol. Cell. Biol., August 1, 2005; 25(15): 6509 - 6520. [Abstract] [Full Text] [PDF]

				L. Chen, H. Yin, B. Farooqi, S. Sebti, A. D. Hamilton, and J. Chen p53 {alpha}-Helix mimetics antagonize p53/MDM2 interaction and activate p53 Mol. Cancer Ther., June 1, 2005; 4(6): 1019 - 1025. [Abstract] [Full Text] [PDF]

				M.-S. Dai and H. Lu Inhibition of MDM2-mediated p53 Ubiquitination and Degradation by Ribosomal Protein L5 J. Biol. Chem., October 22, 2004; 279(43): 44475 - 44482. [Abstract] [Full Text] [PDF]

				X. Wu, L. Yen, L. Irwin, C. Sweeney, and K. L. Carraway III Stabilization of the E3 Ubiquitin Ligase Nrdp1 by the Deubiquitinating Enzyme USP8 Mol. Cell. Biol., September 1, 2004; 24(17): 7748 - 7757. [Abstract] [Full Text] [PDF]

				A. Datta, A. Nag, W. Pan, N. Hay, A. L. Gartel, O. Colamonici, Y. Mori, and P. Raychaudhuri Myc-ARF (Alternate Reading Frame) Interaction Inhibits the Functions of Myc J. Biol. Chem., August 27, 2004; 279(35): 36698 - 36707. [Abstract] [Full Text] [PDF]

				M. O. J. Olson Sensing Cellular Stress: Another New Function for the Nucleolus? Sci. Signal., March 16, 2004; 2004(224): pe10 - pe10. [Abstract] [Full Text] [PDF]

				Y. Zhang, G. W. Wolf, K. Bhat, A. Jin, T. Allio, W. A. Burkhart, and Y. Xiong Ribosomal Protein L11 Negatively Regulates Oncoprotein MDM2 and Mediates a p53-Dependent Ribosomal-Stress Checkpoint Pathway Mol. Cell. Biol., December 1, 2003; 23(23): 8902 - 8912. [Abstract] [Full Text] [PDF]

				K. O'Keefe, H. Li, and Y. Zhang Nucleocytoplasmic Shuttling of p53 Is Essential for MDM2-Mediated Cytoplasmic Degradation but Not Ubiquitination Mol. Cell. Biol., September 15, 2003; 23(18): 6396 - 6405. [Abstract] [Full Text] [PDF]

				Y. Pan and J. Chen MDM2 Promotes Ubiquitination and Degradation of MDMX Mol. Cell. Biol., August 1, 2003; 23(15): 5113 - 5121. [Abstract] [Full Text] [PDF]

				J. Dong, R. G. Phelps, R. Qiao, S. Yao, O. Benard, Z. Ronai, and S. A. Aaronson BRAF Oncogenic Mutations Correlate with Progression rather than Initiation of Human Melanoma Cancer Res., July 15, 2003; 63(14): 3883 - 3885. [Abstract] [Full Text] [PDF]

				C. Wang and J. Chen Phosphorylation and hsp90 Binding Mediate Heat Shock Stabilization of p53 J. Biol. Chem., January 10, 2003; 278(3): 2066 - 2071. [Abstract] [Full Text] [PDF]

				A. Datta, A. Nag, and P. Raychaudhuri Differential Regulation of E2F1, DP1, and the E2F1/DP1 Complex by ARF Mol. Cell. Biol., December 15, 2002; 22(24): 8398 - 8408. [Abstract] [Full Text] [PDF]

				Z. Lai, T. Yang, Y. B. Kim, T. M. Sielecki, M. A. Diamond, P. Strack, M. Rolfe, M. Caligiuri, P. A. Benfield, K. R. Auger, et al. Differentiation of Hdm2-mediated p53 ubiquitination and Hdm2 autoubiquitination activity by small molecular weight inhibitors PNAS, November 12, 2002; 99(23): 14734 - 14739. [Abstract] [Full Text] [PDF]

				C. Li, L. Chen, and J. Chen DNA Damage Induces MDMX Nuclear Translocation by p53-Dependent and -Independent Mechanisms Mol. Cell. Biol., November 1, 2002; 22(21): 7562 - 7571. [Abstract] [Full Text] [PDF]

				Y. Higashi, M. Asanuma, I. Miyazaki, M. E. Haque, N. Fujita, K.-i. Tanaka, and N. Ogawa The p53-activated Gene, PAG608, Requires a Zinc Finger Domain for Nuclear Localization and Oxidative Stress-induced Apoptosis J. Biol. Chem., October 25, 2002; 277(44): 42224 - 42232. [Abstract] [Full Text] [PDF]

				P. R. Nambiar, C. Giardina, K. Guda, W. Aizu, R. Raja, and D. W. Rosenberg Role of the Alternating Reading Frame (P19)-p53 Pathway in an in Vivo Murine Colon Tumor Model Cancer Res., July 1, 2002; 62(13): 3667 - 3674. [Abstract] [Full Text] [PDF]

				L. Heron-Milhavet and D. LeRoith Insulin-like Growth Factor I Induces MDM2-dependent Degradation of p53 via the p38 MAPK Pathway in Response to DNA Damage J. Biol. Chem., May 3, 2002; 277(18): 15600 - 15606. [Abstract] [Full Text] [PDF]

				J. Smeds, P. Berggren, X. Ma, Z. Xu, K. Hemminki, and R. Kumar Genetic status of cell cycle regulators in squamous cell carcinoma of the oesophagus: the CDKN2A (p16INK4a and p14ARF ) and p53 genes are major targets for inactivation Carcinogenesis, April 1, 2002; 23(4): 645 - 655. [Abstract] [Full Text] [PDF]

				W. Lu, J. Lin, and J. Chen Expression of p14ARF Overcomes Tumor Resistance to p53 Cancer Res., March 1, 2002; 62(5): 1305 - 1310. [Abstract] [Full Text] [PDF]

				J. Dang, M.-L. Kuo, C. M. Eischen, L. Stepanova, C. J. Sherr, and M. F. Roussel The RING Domain of Mdm2 Can Inhibit Cell Proliferation Cancer Res., February 1, 2002; 62(4): 1222 - 1230. [Abstract] [Full Text] [PDF]

				D. Tolbert, X. Lu, C. Yin, M. Tantama, and T. Van Dyke p19ARF Is Dispensable for Oncogenic Stress-Induced p53-Mediated Apoptosis and Tumor Suppression In Vivo Mol. Cell. Biol., January 1, 2002; 22(1): 370 - 377. [Abstract] [Full Text] [PDF]

				E. Querido, P. Blanchette, Q. Yan, T. Kamura, M. Morrison, D. Boivin, W. G. Kaelin, R. C. Conaway, J. W. Conaway, and P. E. Branton Degradation of p53 by adenovirus E4orf6 and E1B55K proteins occurs via a novel mechanism involving a Cullin-containing complex Genes & Dev., December 1, 2001; 15(23): 3104 - 3117. [Abstract] [Full Text] [PDF]

				Y. Zhang and Y. Xiong A p53 Amino-Terminal Nuclear Export Signal Inhibited by DNA Damage-Induced Phosphorylation Science, June 8, 2001; 292(5523): 1910 - 1915. [Abstract] [Full Text] [PDF]