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

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    Authors
    Ohtani, Naoko
    Brennan, Paul
    Gaubatz, Stefan
    Sanij, Elaine
    Hertzog, Paul
    Wolvetang, Ernst
    Ghysdael, Jacques
    Rowe, Martin
    Hara, Eiji
    Affiliation
    Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, UK.
    Issue Date
    2003-07-21
    
    Metadata
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    Abstract
    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.
    Citation
    Epstein-Barr virus LMP1 blocks p16INK4a-RB pathway by promoting nuclear export of E2F4/5. 2003, 162 (2):173-83 J. Cell Biol.
    Journal
    The Journal of Cell Biology
    URI
    http://hdl.handle.net/10541/82342
    DOI
    10.1083/jcb.200302085
    PubMed ID
    12860972
    Type
    Article
    Language
    en
    ISSN
    0021-9525
    ae974a485f413a2113503eed53cd6c53
    10.1083/jcb.200302085
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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