This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a colleague Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via ISI Web of Science (12) Citing Articles via Google Scholar Google Scholar Articles by Knight, J. S. Articles by Robertson, E. S. Search for Related Content PubMed PubMed Citation Articles by Knight, J. S. Articles by Robertson, E. S. Social Bookmarking                What's this?

 Previous Article  | Table of Contents |  Next Article 

MEDICAL SCIENCES
Epstein–Barr virus latent antigen 3C can mediate the degradation of the retinoblastoma protein through an SCF cellular ubiquitin ligase

Jason S. Knight, Nikhil Sharma, and Erle S. Robertson ^*

Department of Microbiology and the Tumor Virology Program, Abramson Comprehensive Cancer Center, University of Pennsylvania, 201E Johnson Pavilion, Philadelphia, PA 19104

Edited by Elliott D. Kieff, Harvard University, Boston, MA and approved October 28, 2005 (received for review May 10, 2005)

Epstein–Barr virus (EBV) stimulates the proliferation of latently infected B cells and promotes lymphoid malignancies in humans. To address the role of EBV latency protein Epstein–Barr nuclear antigen 3C (EBNA3C) in regulation of the retinoblastoma protein (Rb), we transfected EBNA3C into 293, BJAB, and SAOS-2 cells. In this context, a dominant effect of EBNA3C is to decrease Rb protein levels. EBNA3C also rescues an Rb-induced flat cell phenotype and targets Rb for proteasome- and ubiquitin-dependent degradation. Further, EBNA3C forms a stable complex with Rb in cells when the proteasome machinery is inhibited and interacts with Rb in vitro, mapping to a conserved domain at the terminus of EBNA3C. Deletion analysis of EBNA3C identified a motif within amino acids 140–149 important for both the binding and regulation of Rb. This motif is of particular interest, because it has also been linked to regulation of the Skp1/Cul1/F-box complex, SCF^Skp2. Indeed, inhibition of Skp2 function with a dominant-negative molecule reduces the ability of EBNA3C to degrade Rb. Skp2 has no detectable effect on Rb levels in the absence of EBNA3C, suggesting that SCF^Skp2 is specifically usurped by EBNA3C for the enhancement of Rb degradation. That EBNA3C has exploited this association suggests that other human malignancies might use a similar strategy to regulate the Rb protein.

retinoblastoma protein | oncogenic viruses | tumor suppressor | cell cycle | ubiquitin–protein ligases

Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: EBV, Epstein–Barr virus; Rb, retinoblastoma protein; EBNA3C, Epstein–Barr nuclear antigen 3C; CMV, cytomegalovirus; HA, hemagglutinin; HEK, human embryonic kidney.

^* To whom correspondence should be addressed. E-mail: erle{at}mail.med.upenn.edu.

© 2005 by The National Academy of Sciences of the USA

CiteULike    Complore    Connotea    Del.icio.us    Digg    What's this?

This article has been cited by other articles in HighWire Press-hosted journals:

				B. G. Bajaj, M. Murakami, Q. Cai, S. C. Verma, K. Lan, and E. S. Robertson Epstein-Barr Virus Nuclear Antigen 3C Interacts with and Enhances the Stability of the c-Myc Oncoprotein J. Virol., April 15, 2008; 82(8): 4082 - 4090. [Abstract] [Full Text] [PDF]

				E. Kashuba, M. Yurchenko, S. P. Yenamandra, B. Snopok, M. Isaguliants, L. Szekely, and G. Klein EBV-encoded EBNA-6 binds and targets MRS18-2 to the nucleus, resulting in the disruption of pRb-E2F1 complexes PNAS, April 8, 2008; 105(14): 5489 - 5494. [Abstract] [Full Text] [PDF]

				K. Lan, S. C. Verma, M. Murakami, B. Bajaj, R. Kaul, and E. S. Robertson Kaposi's sarcoma herpesvirus-encoded latency-associated nuclear antigen stabilizes intracellular activated Notch by targeting the Sel10 protein PNAS, October 9, 2007; 104(41): 16287 - 16292. [Abstract] [Full Text] [PDF]

				K. Huh, X. Zhou, H. Hayakawa, J.-Y. Cho, T. A. Libermann, J. Jin, J. Wade Harper, and K. Munger Human Papillomavirus Type 16 E7 Oncoprotein Associates with the Cullin 2 Ubiquitin Ligase Complex, Which Contributes to Degradation of the Retinoblastoma Tumor Suppressor J. Virol., September 15, 2007; 81(18): 9737 - 9747. [Abstract] [Full Text] [PDF]

				M. B. Gill, J. L. Kutok, and J. D. Fingeroth Epstein-Barr Virus Thymidine Kinase Is a Centrosomal Resident Precisely Localized to the Periphery of Centrioles J. Virol., June 15, 2007; 81(12): 6523 - 6535. [Abstract] [Full Text] [PDF]

				C. Munoz-Fontela, M. A. Garcia, M. Collado, L. Marcos-Villar, P. Gallego, M. Esteban, and C. Rivas Control of virus infection by tumour suppressors Carcinogenesis, June 1, 2007; 28(6): 1140 - 1144. [Abstract] [Full Text] [PDF]

				S. Maruo, Y. Wu, S. Ishikawa, T. Kanda, D. Iwakiri, and K. Takada Epstein-Barr virus nuclear protein EBNA3C is required for cell cycle progression and growth maintenance of lymphoblastoid cells PNAS, December 19, 2006; 103(51): 19500 - 19505. [Abstract] [Full Text] [PDF]

				R. T. Nitta, S. A. Jameson, B. A. Kudlow, L. A. Conlan, and B. K. Kennedy Stabilization of the Retinoblastoma Protein by A-Type Nuclear Lamins Is Required for INK4A-Mediated Cell Cycle Arrest. Mol. Cell. Biol., July 1, 2006; 26(14): 5360 - 5372. [Abstract] [Full Text] [PDF]

				M. Barry and K. Fruh Viral Modulators of Cullin RING Ubiquitin Ligases: Culling the Host Defense Sci. Signal., May 16, 2006; 2006(335): pe21 - pe21. [Abstract] [Full Text] [PDF]

Current Issue | Archives | Online Submission | Info for Authors | Editorial Board | About Subscribe | Advertise | Contact | Site Map Copyright © 2005 by the National Academy of Sciences