EBNA3C Can Modulate the Activities of the Transcription Factor Necdin in Association with Metastasis Suppressor Protein Nm23-H1
EBNA3C Can Modulate the Activities of the Transcription Factor Necdin in Association with Metastasis Suppressor Protein Nm23-H1
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DOI：
10.1128/jvi.02286-08
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发表时间：
2009-05-15
影响因子：
5.4
通讯作者：
Robertson, Erle S.
中科院分区：
文献类型：
--
作者：
Kaul, Rajeev;Murakami, Masanao;Robertson, Erle S.
以前的研究已经证明了体外和体内EB病毒（EBV）核抗原3C（EBNA 3C）和转移抑制因子Nm 23-H1之间的相互作用（C. Subramanian，M. A. Cotter II和E. S. Robertson，Nat.Med.7：350-355，2001）。重要的是，EBNA 3C可以逆转Nm 23-H1在体外抑制人类细胞迁移的能力。EBNA 3C通过调节许多细胞和病毒启动子的转录以及靶向和改变转移抑制因子Nm 23-H1的转录活性而促成EBV相关的人类癌症。此外，Necdin是一种在终末分化细胞中高度诱导的细胞蛋白;它有助于调节细胞生长，并且还已知与病毒癌蛋白相互作用。在这份报告中，我们表明，Nm 23-H1和EBNA 3C可以调节Necdin在EBV感染和转化的背景下的生物学功能。Necdin的水平在EBV阳性细胞中始终较低，EBNA 3C可以改变Necdin的亚细胞定位，并从Necdin介导的抗血管生成和抗增殖作用中拯救细胞。我们还表明Necdin直接与Nm 23-H1相互作用，导致Nm 23-H1的生化功能以及Necdin的生物学功能的调节。EBNA 3C和Nm 23-H1不仅能够挽救Necdin介导的下游血管内皮生长因子启动子的转录抑制，还能够挽救Necdin介导的对癌细胞的生长抑制和抗血管生成作用。这种反应的大部分是通过Necdin的氨基酸残基191至222介导的，其也已知对于核基质靶向是重要的。这些研究表明Necdin在病毒相关人类癌症的低氧环境中调节下游细胞靶点中的作用。
Previous studies have demonstrated the interaction between the Epstein-Barr virus (EBV) nuclear antigen 3C (EBNA3C) and the metastatic suppressor Nm23-H1 both in vitro and in vivo (C. Subramanian, M. A. Cotter II, and E. S. Robertson, Nat. Med. 7: 350-355, 2001). Importantly EBNA3C can reverse the ability of Nm23-H1 to suppress migration of human cells in vitro. EBNA3C contributes to EBV-associated human cancers by regulating transcription of a number of cellular and viral promoters as well as targeting and altering the transcription activities of the metastasis suppressor Nm23-H1. Furthermore, Necdin is a cellular protein which is highly induced in terminally differentiated cells; it contributes to the regulation of cell growth and is also known to interact with viral oncoproteins. In this report, we show that Nm23-H1 and EBNA3C can modulate the biological functions of Necdin in the context of EBV infection and transformation. The levels of Necdin were consistently lower in EBV-positive cells, and EBNA3C could change the subcellular localization of Necdin as well as rescue cells from the antiangiogenic and antiproliferative effects mediated by Necdin. We also show that Necdin directly interacts with Nm23-H1, resulting in modulation of the biochemical function of Nm23-H1 as well as the biological function of Necdin. Both EBNA3C and Nm23-H1 were able to rescue not only Necdin-mediated transcriptional repression of the downstream vascular endothelial growth factor promoter but also Necdin-mediated growth suppression and antiangiogenic effects on cancer cells. The majority of this response was mediated through amino acid residues 191 to 222 of Necdin, which are also known to be important for nuclear matrix targeting. These studies suggest a role for Necdin in the regulation of downstream cellular targets in a hypoxic environment in virus-associated human cancers.