Parker G A, Crook T, Bain M, Sara E A, Farrell P J, Allday M J
Department of Medical Microbiology, Imperial College School of Medicine at St Mary's, London.
Oncogene. 1996 Dec 19;13(12):2541-9.
Epstein-Barr virus (EBV) requires six genes to efficiently immortalize human B cells. We have shown that one of these, EBNA3C, can cooperate with activated (Ha-)ras in co-transfection assays to immortalize and transform rat embryo fibroblasts (REFs). EBNA3C also augmented transformation by (Ha-)ras and a mutant p53 to a similar extent as human papilloma virus E7. As with E7 this effect was not inhibited by cotransfection with the cyclin-dependent kinase inhibitor (CDKI), a p16INK4A, which can normally activate the retinoblastoma protein (pRb) and induce growth arrest. Also like E7/ras and E1A/ras transformed cells the EBNA3C/ras transformants are very susceptible to apoptotic cell death. In vitro EBNA3C binds to pRb in a manner which is dependent on the integrity of the pocket domain; this suggests that EBNA3C, even though it lacks the LXCXE pRb binding motif found in E7 and E1A, may interact with pRb in vivo. We conclude that EBNA3C functions as an oncoprotein which directs cell cycle progression through the G1 phase restriction point when conditions might signal arrest. For the first time this demonstrates that EBV encodes a protein, functionally but not necessarily mechanistically, similar to the pRb-neutralizing nuclear antigens encoded by the 'small' DNA tumor viruses.
爱泼斯坦-巴尔病毒（EBV）需要六个基因才能有效地使人类B细胞永生化。我们已经表明，其中一个基因EBNA3C，在共转染实验中可以与活化的（Ha-）ras协同作用，使大鼠胚胎成纤维细胞（REFs）永生化并转化。EBNA3C还能增强（Ha-）ras和突变型p53的转化作用，其程度与人类乳头瘤病毒E7相似。与E7一样，这种作用不会被与细胞周期蛋白依赖性激酶抑制剂（CDKI），即p16INK4A共转染所抑制，p16INK4A通常可以激活视网膜母细胞瘤蛋白（pRb）并诱导生长停滞。同样与E7/ras和E1A/ras转化细胞一样，EBNA3C/ras转化体对凋亡性细胞死亡非常敏感。在体外，EBNA3C以一种依赖于口袋结构域完整性的方式与pRb结合；这表明EBNA3C尽管缺乏E7和E1A中发现的LXCXE pRb结合基序，但可能在体内与pRb相互作用。我们得出结论，EBNA3C作为一种癌蛋白，在可能发出停滞信号的情况下，指导细胞周期通过G1期限制点进行进展。这首次证明EBV编码一种在功能上但不一定在机制上类似于“小”DNA肿瘤病毒编码的pRb中和核抗原的蛋白质。
