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Epstein-Barr virus LMP1 blocks p16INK4a-RB pathway by promoting nuclear export of E2F4/5
Naoko Ohtani1, Paul Brennan, Stefan Gaubatz
1Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, UK.
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.
Insights
Epstein-Barr virus (EBV) protein LMP1 represses the p16INK4a-RB pathway by exporting transcription factors Ets2 and E2F4/5 from the nucleus. This dual action blocks p16INK4a expression and its downstream cell cycle arrest effects.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- The p16INK4a-RB pathway is crucial for cell cycle control and is frequently disrupted by viral oncoproteins.
- Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is vital for EBV-mediated immortalization and transformation.
- LMP1, unlike other viral oncoproteins, inhibits p16INK4a expression without binding the retinoblastoma protein.
Purpose of the Study:
- To elucidate the mechanism by which EBV's LMP1 represses p16INK4a tumor suppressor gene expression.
- To investigate LMP1's impact on key transcription factors regulating the p16INK4a-RB pathway.
Main Methods:
- Investigated the role of CRM1-dependent nuclear export in LMP1's function.
- Analyzed the effect of LMP1 on the nuclear localization and expression levels of Ets2, E2F4, and E2F5.
- Assessed the impact of LMP1-mediated nuclear export on p16INK4a expression and cell cycle arrest.
Main Results:
- LMP1 promotes the CRM1-dependent nuclear export of Ets2, a transcription factor essential for p16INK4a gene expression.
- LMP1 also induces the CRM1-dependent nuclear export of E2F4/5 transcription factors, which mediate p16INK4a-induced cell cycle arrest.
- These actions lead to reduced p16INK4a expression and impaired downstream cell cycle regulation.
Conclusions:
- LMP1 employs a novel mechanism involving CRM1-dependent nuclear export to disrupt the p16INK4a-RB pathway.
- LMP1's effects include direct repression of p16INK4a expression and inhibition of its downstream mediators.
- This study enhances understanding of how viral oncoproteins manipulate host cell cycle control mechanisms.