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dc.contributor.authorOhtani, Naoko
dc.contributor.authorBrennan, Paul
dc.contributor.authorGaubatz, Stefan
dc.contributor.authorSanij, Elaine
dc.contributor.authorHertzog, Paul
dc.contributor.authorWolvetang, Ernst
dc.contributor.authorGhysdael, Jacques
dc.contributor.authorRowe, Martin
dc.contributor.authorHara, Eiji
dc.date.accessioned2009-09-23T13:50:42Z
dc.date.available2009-09-23T13:50:42Z
dc.date.issued2003-07-21
dc.identifier.citationEpstein-Barr virus LMP1 blocks p16INK4a-RB pathway by promoting nuclear export of E2F4/5. 2003, 162 (2):173-83 J. Cell Biol.en
dc.identifier.issn0021-9525
dc.identifier.pmid12860972
dc.identifier.doi10.1083/jcb.200302085
dc.identifier.urihttp://hdl.handle.net/10541/82342
dc.description.abstractThe 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.
dc.language.isoenen
dc.subject.meshActive Transport, Cell Nucleus
dc.subject.meshB-Lymphocytes
dc.subject.meshCell Line
dc.subject.meshCell Line, Transformed
dc.subject.meshCell Nucleus
dc.subject.meshCyclin-Dependent Kinase Inhibitor p16
dc.subject.meshCytoplasm
dc.subject.meshDNA-Binding Proteins
dc.subject.meshE2F4 Transcription Factor
dc.subject.meshE2F5 Transcription Factor
dc.subject.meshFibroblasts
dc.subject.meshGene Expression Regulation
dc.subject.meshHumans
dc.subject.meshKaryopherins
dc.subject.meshProtein Structure, Tertiary
dc.subject.meshReceptors, Cytoplasmic and Nuclear
dc.subject.meshTranscription Factors
dc.subject.meshTransfection
dc.subject.meshViral Matrix Proteins
dc.titleEpstein-Barr virus LMP1 blocks p16INK4a-RB pathway by promoting nuclear export of E2F4/5.en
dc.typeArticleen
dc.contributor.departmentPaterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, UK.en
dc.identifier.journalThe Journal of Cell Biologyen
html.description.abstractThe 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.


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