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Published online 14 July 2003. doi:10.1083/jcb.200302085
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© The Rockefeller University Press, 0021-9525/2003/7/173 $5.00
The Journal of Cell Biology, Volume 162, Number 2, 173-183

Article

 Epstein-Barr virus LMP1 blocks p16INK4a–RB pathway by promoting nuclear export of E2F4/5

Naoko Ohtani1, Paul Brennan2, Stefan Gaubatz3, Elaine Sanij4, Paul Hertzog4, Ernst Wolvetang4, Jacques Ghysdael5, Martin Rowe2 and Eiji Hara1,6

1 Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, UK
2 Section of Infection and Immunity, University of Wales College of Medicine, Cardiff CF4 4XX, UK
3 Institute for Molecular Biology and Tumor Research, Philipps-University Marburg, 35037 Marburg, Germany
4 Centre for Functional Genomics and Human Disease, Monash Institute of Reproduction and Development, Monash University, Clayton, Victoria 3800, Australia
5 CNRS UMR 146, Institut Curie Centre Universitaire, bat 110 91405 Orsay, France
6 Division of Protein Information, Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan

Address correspondence to Eiji Hara, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, UK. Tel.: 44-161-446-3122. Fax: 44-161-446-3075. E-mail: Ehara{at}picr.man.ac.uk

The p16INK4a–RB pathway plays a critical role in preventing inappropriate cell proliferation and is often targeted by viral oncoproteins during immortalization. Latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) is often present in EBV-associated proliferative diseases and is critical for the immortalizing and transforming activity of EBV. Unlike other DNA tumor virus oncoproteins, which possess immortalizing activity, LMP1 does not bind to retinoblastoma tumor suppressor protein, but instead blocks the expression of p16INK4a tumor suppressor gene. However, it has been unclear how LMP1 represses the p16INK4a gene expression. Here, we report that LMP1 promotes the CRM1-dependent nuclear export of Ets2, which is an important transcription factor for p16INK4a gene expression, thereby reducing the level of p16INK4a expression. We further demonstrate that LMP1 also blocks the function of E2F4 and E2F5 (E2F4/5) transcription factors through promoting their nuclear export in a CRM1-dependent manner. As E2F4/5 are essential downstream mediators for a p16INK4a-induced cell cycle arrest, these results indicate that the action of LMP1 on nuclear export has two effects on the p16INK4a–RB pathway: (1) repression of p16INK4a expression and (2) blocking the downstream mediator of the p16INK4a–RB pathway. These results reveal a novel activity of LMP1 and increase an understanding of how viral oncoproteins perturb the p16INK4a–RB pathway.

Key Words: cell cycle; immortalization; Cdk; Ets; senescence

* Abbreviations used in this paper: ChIP, chromatin-immunoprecipitation; E2F4/5, E2F4 and E2F5; EBV, Epstein-Barr virus; HDF, human diploid fibroblast; LMB, leptomycin B; LMP1, latent membrane protein 1; MEF, mouse embryonic fibroblast; MEK, MAPK/ERK kinase; NES, nuclear export signal; pRB, retinoblastoma tumor suppressor protein.


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