Institute for Molecular Virology, Saint Louis University Health Sciences Center, Doisy Research Center, 1100 South Grand Blvd., Saint Louis, MO 63104, USA.
Virology. 2013 Sep 1;443(2):313-20. doi: 10.1016/j.virol.2013.05.018. Epub 2013 Jun 5.
Adenovirus E1A induces cell proliferation, oncogenic transformation and promotes viral replication through interaction with p300/CBP, TRRAP/p400 multi-protein complex and the retinoblastoma (pRb) family proteins through distinct domains in the E1A N-terminal region. The C-terminal region of E1A suppresses E1A/Ras co-transformation and interacts with FOXK1/K2, DYRK1A/1B/HAN11 and CtBP1/2 (CtBP) protein complexes. To specifically dissect the role of CtBP interaction with E1A, we engineered a mutation (DL→AS) within the CtBP-binding motif, PLDLS, and investigated the effect of the mutation on immortalization and Ras cooperative transformation of primary cells and viral replication. Our results suggest that CtBP-E1A interaction suppresses immortalization and Ras co-operative transformation of primary rodent epithelial cells without significantly influencing the tumorigenic activities of transformed cells in immunodeficient and immunocompetent animals. During productive infection, CtBP-E1A interaction enhances viral replication in human cells. Between the two CtBP family proteins, CtBP2 appears to restrict viral replication more than CtBP1 in human cells.
腺病毒 E1A 通过与 p300/CBP、TRRAP/p400 多蛋白复合物以及视网膜母细胞瘤 (pRb) 家族蛋白相互作用，在 E1A N 端区域的不同结构域中诱导细胞增殖、致癌转化和促进病毒复制。E1A 的 C 端区域抑制 E1A/Ras 共转化，并与 FOXK1/K2、DYRK1A/1B/HAN11 和 CtBP1/2（CtBP）蛋白复合物相互作用。为了专门剖析 CtBP 与 E1A 相互作用的作用，我们在 CtBP 结合基序 PLDLS 内设计了一个突变（DL→AS），并研究了该突变对原代细胞永生化和 Ras 协同转化以及病毒复制的影响。我们的结果表明，CtBP-E1A 相互作用抑制了原代啮齿动物上皮细胞的永生化和 Ras 协同转化，而对免疫缺陷和免疫功能正常动物中转化细胞的致瘤活性没有显著影响。在产毒感染过程中，CtBP-E1A 相互作用增强了人细胞中的病毒复制。在两种 CtBP 家族蛋白中，CtBP2 似乎比 CtBP1 更能限制人细胞中的病毒复制。
