Ohtani Naoko, Brennan Paul, Gaubatz Stefan, Sanij Elaine, Hertzog Paul, Wolvetang Ernst, Ghysdael Jacques, Rowe Martin, Hara Eiji
Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, UK.
J Cell Biol. 2003 Jul 21;162(2):173-83. doi: 10.1083/jcb.200302085. Epub 2003 Jul 14.
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.
p16INK4a-RB通路在防止细胞异常增殖中起关键作用，在细胞永生化过程中常被病毒癌蛋白靶向作用。爱泼斯坦-巴尔病毒（EBV）的潜伏膜蛋白1（LMP1）常存在于EBV相关增殖性疾病中，对EBV的永生化和转化活性至关重要。与其他具有永生化活性的DNA肿瘤病毒癌蛋白不同，LMP1不与视网膜母细胞瘤肿瘤抑制蛋白结合，而是阻断p16INK4a肿瘤抑制基因的表达。然而，LMP1如何抑制p16INK4a基因表达尚不清楚。在此，我们报告LMP1促进Ets2依赖CRM1的核输出，Ets2是p16INK4a基因表达的重要转录因子，从而降低p16INK4a表达水平。我们进一步证明，LMP1还通过以CRM1依赖的方式促进E2F4和E2F5（E2F4/5）转录因子的核输出，阻断其功能。由于E2F4/5是p16INK4a诱导的细胞周期停滞的重要下游介质，这些结果表明LMP1对核输出的作用对p16INK4a-RB通路有两个影响：（1）抑制p16INK4a表达；（2）阻断p16INK4a-RB通路的下游介质。这些结果揭示了LMP1的一种新活性，并增进了对病毒癌蛋白如何扰乱p16INK4a-RB通路的理解。
