Dissection of the C-Terminal Region of E1A Redefines the Roles of CtBP and Other Cellular Targets in Oncogenic Transformation
Dissection of the C-Terminal Region of E1A Redefines the Roles of CtBP and Other Cellular Targets in Oncogenic Transformation
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DOI：
10.1128/jvi.00786-13
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发表时间：
2013-09-01
影响因子：
5.4
通讯作者：
Mymryk, J. S.
中科院分区：
文献类型：
--
作者：
Cohen, M. J.;Yousef, A. F.;Mymryk, J. S.
人腺病毒E1 A与细胞蛋白质相互作用网络有着广泛的联系。通过这样做，E1 A可以操纵许多细胞程序，包括细胞周期进程。通过这些重编程事件，E1 A作为一种促进生长的癌基因发挥作用，并已被广泛用于研究有助于肿瘤发生的机制。然而，目前还不清楚E1 A的C-末端区域如何促进致癌转化。虽然该区域是与E1 B合作进行转化所必需的，但矛盾的是，它与激活的Ras合作抑制转化。先前的分析表明，E1 A与CtBP的相互作用在这两种活动中起着关键作用。然而，E1 A的一些C-末端突变体保留CtBP结合，但在转化中表现出缺陷，这表明该区域的其他靶标也是必要的。为了探索这些额外的因素的作用，我们进行了广泛的突变分析的C末端的E1 A。我们确定了结合E1 A C末端所有已知靶标所需的关键残基。我们进一步测试了每种突变体与E1 B-55 K或Ras合作定位于细胞核和转化原代大鼠细胞的能力。E1 A与输入素α 3/Qip 1、双特异性酪氨酸调节激酶1A（DYRK 1A）、HAN 11和CtBP的相互作用影响E1 B-55 K的转化。有趣的是，E1 A与DYRK 1A和HAN 11的相互作用似乎在抑制活化Ras的转化中起作用，而与CtBP的相互作用不是必需的。这一意想不到的结果表明，需要修改现有的模型，并提供了新的见解E1 A的C末端的转化。
Human adenovirus E1A makes extensive connections with the cellular protein interaction network. By doing so, E1A can manipulate many cellular programs, including cell cycle progression. Through these reprogramming events, E1A functions as a growth-promoting oncogene and has been used extensively to investigate mechanisms contributing to oncogenesis. Nevertheless, it remains unclear how the C-terminal region of E1A contributes to oncogenic transformation. Although this region is required for transformation in cooperation with E1B, it paradoxically suppresses transformation in cooperation with activated Ras. Previous analysis has suggested that the interaction of E1A with CtBP plays a pivotal role in both activities. However, some C-terminal mutants of E1A retain CtBP binding and yet exhibit defects in transformation, suggesting that other targets of this region are also necessary. To explore the roles of these additional factors, we performed an extensive mutational analysis of the C terminus of E1A. We identified key residues that are specifically required for binding all known targets of the C terminus of E1A. We further tested each mutant for the ability to both localize to the nucleus and transform primary rat cells in cooperation with E1B-55K or Ras. Interaction of E1A with importin alpha 3/Qip1, dual-specificity tyrosine-regulated kinase 1A (DYRK1A), HAN11, and CtBP influenced transformation with E1B-55K. Interestingly, the interaction of E1A with DYRK1A and HAN11 appeared to play a role in suppression of transformation by activated Ras whereas interaction with CtBP was not necessary. This unexpected result suggests a need for revision of current models and provides new insight into transformation by the C terminus of E1A.