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In Vivo Ubiquitination and Proteasome-mediated Degradation of p53¹

Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115

The levels of the tumor suppressor protein p53 are generally quite low in normal cells, due in part to its rapid turnover. Previous studies have implicated ubiquitin-dependent proteolysis in the turnover of wild-type p53 but have not established whether or not p53 is itself a substrate of the ubiquitin system. In this study, inhibitors of the 26S proteasome have been used to further explore the role of ubiquitin proteolysis in regulating p53 turnover. Increased levels of the tumor suppressor protein p53 were observed in normal cells, as well as in cells expressing the human papillomavirus 16 E6 oncoprotein, on exposure of the cells to proteasome inhibitors. Pulse-chase experiments indicated that the increased p53 levels resulted from stabilization of the protein. Furthermore, ubiquitin-p53 conjugates were detected in untreated as well as -irradiated cells, indicating that ubiquitin-dependent proteolysis plays a role in the normal turnover of p53. Increased levels of the cyclin:cyclin-dependent kinase inhibitor p21, a downstream effector of p53 function, were also observed in proteasome inhibitor-treated cells, and this increase was due in part to an increase in p21 mRNA.

¹ This work was supported by NIH Grants P01-CA-50661-07 and RO1-CA64888-1 (P. M. H.).

² Present address: Department of Biochemistry, Rutgers University, Piscataway, NJ.

³ To whom requests for reprints should be addressed, at Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115. Phone: (617) 432-2884; Fax: (617) 432-2882.

Received 1/23/96. Accepted 4/ 1/96.

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				Y. Y. Degenhardt and S. J. Silverstein Gps2, a Protein Partner for Human Papillomavirus E6 Proteins J. Virol., January 1, 2001; 75(1): 151 - 160. [Abstract] [Full Text]

				R. J. Klasa, A. F. List, and B. D. Cheson Rational Approaches to Design of Therapeutics Targeting Molecular Markers Hematology, January 1, 2001; 2001(1): 443 - 462. [Abstract] [Full Text] [PDF]

				S. Nakamura, J. A. Roth, and T. Mukhopadhyay Multiple Lysine Mutations in the C-Terminal Domain of p53 Interfere with MDM2-Dependent Protein Degradation and Ubiquitination Mol. Cell. Biol., December 15, 2000; 20(24): 9391 - 9398. [Abstract] [Full Text]

				M. S. Rodriguez, J. M. P. Desterro, S. Lain, D. P. Lane, and R. T. Hay Multiple C-Terminal Lysine Residues Target p53 for Ubiquitin-Proteasome-Mediated Degradation Mol. Cell. Biol., November 15, 2000; 20(22): 8458 - 8467. [Abstract] [Full Text]

				J.-R. J. Yeh, R. Mohan, and C. M. Crews The antiangiogenic agent TNP-470 requires p53 and p21CIP/WAF for endothelial cell growth arrest PNAS, November 7, 2000; 97(23): 12782 - 12787. [Abstract] [Full Text] [PDF]

				M. V. BLAGOSKLONNY p53 from complexity to simplicity: mutant p53 stabilization, gain-of-function, and dominant-negative effect FASEB J, October 1, 2000; 14(13): 1901 - 1907. [Abstract] [Full Text]

				B. O. Petersen, C. Wagener, F. Marinoni, E. R. Kramer, M. Melixetian, E. L. Denchi, C. Gieffers, C. Matteucci, J.-M. Peters, and K. Helin Cell cycle- and cell growth-regulated proteolysis of mammalian CDC6 is dependent on APC-CDH1 Genes & Dev., September 15, 2000; 14(18): 2330 - 2343. [Abstract] [Full Text]

				A. Frankel, S. Man, P. Elliott, J. Adams, and R. S. Kerbel Lack of Multicellular Drug Resistance Observed in Human Ovarian and Prostate Carcinoma Treated with the Proteasome Inhibitor PS-341 Clin. Cancer Res., September 1, 2000; 6(9): 3719 - 3728. [Abstract] [Full Text]

				C. Chen, H. Lin, C. Karanes, G. R. Pettit, and B. D. Chen Human THP-1 Monocytic Leukemic Cells Induced to Undergo Monocytic Differentiation by Bryostatin 1 Are Refractory to Proteasome Inhibitor-induced Apoptosis Cancer Res., August 1, 2000; 60(16): 4377 - 4385. [Abstract] [Full Text]

				P. Masdehors, H. Merle-Beral, K. Maloum, S. Omura, H. Magdelenat, and J. Delic Deregulation of the ubiquitin system and p53 proteolysis modify the apoptotic response in B-CLL lymphocytes Blood, July 1, 2000; 96(1): 269 - 274. [Abstract] [Full Text] [PDF]

				Y. Nakanishi, X.-H. Pei, K. Takayama, F. Bai, M. Izumi, K. Kimotsuki, K. Inoue, T. Minami, H. Wataya, and N. Hara Polycyclic Aromatic Hydrocarbon Carcinogens Increase Ubiquitination of p21 Protein after the Stabilization of p53 and the Expression of p21 Am. J. Respir. Cell Mol. Biol., June 1, 2000; 22(6): 747 - 754. [Abstract] [Full Text]

				F. Chen, D. Chang, M. Goh, S. A. Klibanov, and M. Ljungman Role of p53 in Cell Cycle Regulation and Apoptosis following Exposure to Proteasome Inhibitors Cell Growth Differ., May 1, 2000; 11(5): 239 - 246. [Abstract] [Full Text]

				I. A. Atencio, M. Ramachandra, P. Shabram, and G. W. Demers Calpain Inhibitor 1 Activates p53-dependent Apoptosis in Tumor Cell Lines Cell Growth Differ., May 1, 2000; 11(5): 247 - 253. [Abstract] [Full Text]

				M. A. Gregory and S. R. Hann c-Myc Proteolysis by the Ubiquitin-Proteasome Pathway: Stabilization of c-Myc in Burkitt's Lymphoma Cells Mol. Cell. Biol., April 1, 2000; 20(7): 2423 - 2435. [Abstract] [Full Text]

				Y. Kudo, T. Takata, I. Ogawa, T. Kaneda, S. Sato, T. Takekoshi, M. Zhao, M. Miyauchi, and H. Nikai p27Kip1 Accumulation by Inhibition of Proteasome Function Induces Apoptosis in Oral Squamous Cell Carcinoma Cells Clin. Cancer Res., March 1, 2000; 6(3): 916 - 923. [Abstract] [Full Text]

				M. Eura, K. Chikamatsu, F. Katsura, A. Obata, Y. Sobao, M. Takiguchi, Y. Song, E. Appella, T. L. Whiteside, and A. B. DeLeo A Wild-type Sequence p53 Peptide Presented by HLA-A24 Induces Cytotoxic T Lymphocytes that Recognize Squamous Cell Carcinomas of the Head and Neck Clin. Cancer Res., March 1, 2000; 6(3): 979 - 986. [Abstract] [Full Text]

				D. H. Chung, K. Ohashi, M. Watanabe, N. Miyasaka, and S. Hirosawa Mannose Trimming Targets Mutant alpha 2-Plasmin Inhibitor for Degradation by the Proteasome J. Biol. Chem., February 18, 2000; 275(7): 4981 - 4987. [Abstract] [Full Text] [PDF]

				J. Gu, D. Chen, J. Rosenblum, R. M. Rubin, and Z.-M. Yuan Identification of a Sequence Element from p53 That Signals for Mdm2-Targeted Degradation Mol. Cell. Biol., February 15, 2000; 20(4): 1243 - 1253. [Abstract] [Full Text]

				V. GOTTIFREDI, S.Y. SHIEH, and C. PRIVES Regulation of p53 after Different Forms of Stress and at Different Cell Cycle Stages Cold Spring Harb Symp Quant Biol, January 1, 2000; 65(0): 483 - 488. [Abstract] [PDF]

				M. Gu and P. Brecher Nitric Oxide-Induced Increase in p21Sdi1/Cip1/Waf1 Expression During the Cell Cycle in Aortic Adventitial Fibroblasts Arterioscler Thromb Vasc Biol, January 1, 2000; 20(1): 27 - 34. [Abstract] [Full Text] [PDF]