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E7 Protein of Human Papilloma Virus-16 Induces Degradation of Retinoblastoma Protein through the Ubiquitin-Proteasome Pathway¹

Department of Radiation Oncology, New England Medical Center [D.E.W., V.B.], and Department of Biochemistry [V.B.] and Genetics Program [S.N.B., V.B.], Tufts University School of Medicine, Boston, Massachusetts 02111

Rb protein is a critical regulator of entry into the cell cycle, and loss of Rb function by deletions, mutations, or interaction with DNA viral oncoproteins leads to oncogenic transformation. We have shown that the human papilloma virus (HPV)-16 E7 gene is sufficient to induce the immortalization of mammary epithelial cells (MECs). Surprisingly, the steady-state level of Rb protein in these immortal cells was drastically decreased. Here, we used pulse-chase analysis to show that the in vivo loss of Rb protein in E7-immortalized MECs is a consequence of enhanced degradation. Expression of HPV16 E7 in a cell line with a temperaturesensitive mutation in the E1 enzyme of the ubiquitin pathway demonstrated that degradation of Rb was ubiquitin dependent. Treatment of E7-immortalized MECs with aldehyde inhibitors of proteasome-associated proteases led to a marked stabilization of Rb protein, particularly the hypophosphorylated form. Taken together, our results provide evidence for HPV-16 E7-induced enhanced degradation of Rb protein via a ubiquitin-proteasome pathway and suggest a second mechanism of oncogenic transformation by E7, in addition to its previously identified ability to sequester Rb from E2F. Our analyses also show that normal Rb levels are regulated by the ubiquitin-proteasome degradation pathway.

¹ This work was supported by NIH Grants CA56803 and CA64823 (to V. B.).

² To whom requests for reprints should be addressed, at Department of Radiation Oncology, New England Medical Center, 750 Washington Street, Boston, MA 02111. Phone: (617) 636-4776; Fax: (617) 636-6205.

Received 7/29/96. Accepted 8/27/96.

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				S. L. Gonzalez, M. Stremlau, X. He, J. R. Basile, and K. Munger Degradation of the Retinoblastoma Tumor Suppressor by the Human Papillomavirus Type 16 E7 Oncoprotein Is Important for Functional Inactivation and Is Separable from Proteasomal Degradation of E7 J. Virol., August 15, 2001; 75(16): 7583 - 7591. [Abstract] [Full Text] [PDF]

				S. Duensing, A. Duensing, E. R. Flores, A. Do, P. F. Lambert, and K. Munger Centrosome Abnormalities and Genomic Instability by Episomal Expression of Human Papillomavirus Type 16 in Raft Cultures of Human Keratinocytes J. Virol., August 15, 2001; 75(16): 7712 - 7716. [Abstract] [Full Text] [PDF]

				A.-M. Helt and D. A. Galloway Destabilization of the Retinoblastoma Tumor Suppressor by Human Papillomavirus Type 16 E7 Is Not Sufficient To Overcome Cell Cycle Arrest in Human Keratinocytes J. Virol., August 1, 2001; 75(15): 6737 - 6747. [Abstract] [Full Text]

				M. Giarrè, S. Caldeira, I. Malanchi, F. Ciccolini, M. J. Leão, and M. Tommasino Induction of pRb Degradation by the Human Papillomavirus Type 16 E7 Protein Is Essential To Efficiently Overcome p16INK4a-Imposed G1 Cell Cycle Arrest J. Virol., May 15, 2001; 75(10): 4705 - 4712. [Abstract] [Full Text]

				J. Kim, D. M. Shin, A. El-Naggar, J. S. Lee, C. Corrales, S. M. Lippman, W. K. Hong, and W. N. Hittelman Chromosome Polysomy and Histological Characteristics in Oral Premalignant Lesions Cancer Epidemiol. Biomarkers Prev., April 1, 2001; 10(4): 319 - 325. [Abstract] [Full Text]

				K. Webster, A. Taylor, and K. Gaston Oestrogen and progesterone increase the levels of apoptosis induced by the human papillomavirus type 16 E2 and E7 proteins J. Gen. Virol., January 1, 2001; 82(1): 201 - 213. [Abstract] [Full Text]

				E. C. Goodwin and D. DiMaio Repression of human papillomavirus oncogenes in HeLa cervical carcinoma cells causes the orderly reactivation of dormant tumor suppressor pathways PNAS, November 7, 2000; 97(23): 12513 - 12518. [Abstract] [Full Text] [PDF]

				L. Wu, E. C. Goodwin, L. K. Naeger, E. Vigo, K. Galaktionov, K. Helin, and D. DiMaio E2F-Rb Complexes Assemble and Inhibit cdc25A Transcription in Cervical Carcinoma Cells following Repression of Human Papillomavirus Oncogene Expression Mol. Cell. Biol., October 1, 2000; 20(19): 7059 - 7067. [Abstract] [Full Text]

				B. Mannhardt, S. A. Weinzimer, M. Wagner, M. Fiedler, P. Cohen, P. Jansen-Dürr, and W. Zwerschke Human Papillomavirus Type 16 E7 Oncoprotein Binds and Inactivates Growth-Inhibitory Insulin-Like Growth Factor Binding Protein 3 Mol. Cell. Biol., September 1, 2000; 20(17): 6483 - 6495. [Abstract] [Full Text]

				W.-M. Chien, J. N. Parker, D.-C. Schmidt-Grimminger, T. R. Broker, and L. T. Chow Casein Kinase II Phosphorylation of the Human Papillomavirus-18 E7 Protein Is Critical for Promoting S-Phase Entry Cell Growth Differ., August 1, 2000; 11(8): 425 - 435. [Abstract] [Full Text]

				W. H. Kao, S. L. Beaudenon, A. L. Talis, J. M. Huibregtse, and P. M. Howley Human Papillomavirus Type 16 E6 Induces Self-Ubiquitination of the E6AP Ubiquitin-Protein Ligase J. Virol., July 15, 2000; 74(14): 6408 - 6417. [Abstract] [Full Text]

				Q. Gao, A. Kumar, S. Srinivasan, L. Singh, H. Mukai, Y. Ono, D. E. Wazer, and V. Band PKN Binds and Phosphorylates Human Papillomavirus E6 Oncoprotein J. Biol. Chem., May 12, 2000; 275(20): 14824 - 14830. [Abstract] [Full Text] [PDF]

				H. z. Hausen Papillomaviruses Causing Cancer: Evasion From Host-Cell Control in Early Events in Carcinogenesis J Natl Cancer Inst, May 3, 2000; 92(9): 690 - 698. [Abstract] [Full Text] [PDF]

				M. N. Aronson, A. D. Meyer, J. Györgyey, L. Katul, H. J. Vetten, B. Gronenborn, and T. Timchenko Clink, a Nanovirus-Encoded Protein, Binds both pRB and SKP1 J. Virol., April 1, 2000; 74(7): 2967 - 2972. [Abstract] [Full Text]

				Q. Chen, V. Tu, J Catania, M Burton, O Toussaint, and T Dilley Involvement of Rb family proteins, focal adhesion proteins and protein synthesis in senescent morphogenesis induced by hydrogen peroxide J. Cell Sci., January 11, 2000; 113(22): 4087 - 4097. [Abstract] [PDF]

				J.-S. Park, S. Boyer, K. Mitchell, D. Gilfor, M. Birrer, G. Darlington, W. El Deiry, G. L. Firestone, K. Munger, V. Band, et al. Expression of Human Papilloma Virus E7 Protein Causes Apoptosis and Inhibits DNA Synthesis in Primary Hepatocytes via Increased Expression of p21Cip-1/WAF1/MDA6 J. Biol. Chem., January 7, 2000; 275(1): 18 - 28. [Abstract] [Full Text] [PDF]

				K. Webster, J. Parish, M. Pandya, P. L. Stern, A. R. Clarke, and K. Gaston The Human Papillomavirus (HPV) 16 E2 Protein Induces Apoptosis in the Absence of Other HPV Proteins and via a p53-dependent Pathway J. Biol. Chem., January 7, 2000; 275(1): 87 - 94. [Abstract] [Full Text] [PDF]

				J. L. Schwartz Biomarkers and Molecular Epidemiology and Chemoprevention of Oral Carcinogenesis Critical Reviews in Oral Biology & Medicine, January 1, 2000; 11(1): 92 - 122. [Abstract] [Full Text] [PDF]

				R. A. Levine and M. A. Fleischli Inactivation of p53 and Retinoblastoma Family Pathways in Canine Osteosarcoma Cell Lines Vet. Pathol., January 1, 2000; 37(1): 54 - 61. [Abstract] [Full Text] [PDF]

				J.-P. Therrien, R. Drouin, C. Baril, and E. A. Drobetsky Human cells compromised for p53 function exhibit defective global and transcription-coupled nucleotide excision repair, whereas cells compromised for pRb function are defective only in global repair PNAS, December 21, 1999; 96(26): 15038 - 15043. [Abstract] [Full Text] [PDF]

				L. Didcock, D. F. Young, S. Goodbourn, and R. E. Randall The V Protein of Simian Virus 5 Inhibits Interferon Signalling by Targeting STAT1 for Proteasome-Mediated Degradation J. Virol., December 1, 1999; 73(12): 9928 - 9933. [Abstract] [Full Text]