Epstein-Barr virus LMP1 blocks p16INK4a-RB pathway by promoting nuclear export of E2F4/5.
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.
Ohtani
Naoko
N
Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, UK.
Brennan
Paul
P
Gaubatz
Stefan
S
Sanij
Elaine
E
Hertzog
Paul
P
Wolvetang
Ernst
E
Ghysdael
Jacques
J
Rowe
Martin
M
Hara
Eiji
E
D021581:Active Transport, Cell Nucleus; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050704:E2F4 Transcription Factor; D050700:E2F5 Transcription Factor; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000821:virology; D005786:Gene Expression Regulation; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000097606:Exportin 1 Protein
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D050704:E2F4 Transcription Factor; D050700:E2F5 Transcription Factor; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014763:Viral Matrix Proteins; D000097606:Exportin 1 Protein; C092558:E2F5 protein, human; C037662:EBV-associated membrane antigen, Epstein-Barr virus