Epstein-Barr virus nuclear antigen 3C interacts with and enhances the stability of the c-Myc oncoprotein
Epstein-Barr virus nuclear antigen 3C interacts with and enhances the stability of the c-Myc oncoprotein
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DOI：
10.1128/jvi.02500-07
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发表时间：
2008-04-01
影响因子：
5.4
通讯作者：
Robertson, Erle S.
中科院分区：
文献类型：
--
作者：
Bajaj, Bharat G.;Murakami, Masanao;Robertson, Erle S.
EB病毒（EBV）是第一个与癌症相关的人类DNA病毒。它的致癌潜力进一步证明了其在体外转化原代B淋巴细胞的能力。EB病毒核抗原3C（EBNA 3C）是一种对人原代B淋巴细胞转化至关重要的潜伏抗原。虽然EBNA 3C已被证明可以调节几种细胞功能，但涉及细胞转化的其他靶点仍有待探索。EBNA 3C可以募集SCFSkp 2泛素连接酶复合物的关键组分。在这份报告中，我们表明EBNA 3C残基130至190，以前显示结合到SCFSkP 2复合物，也可以强烈地与c-Myc癌蛋白。此外，EBNA 3C与c-Myc的相互作用被定位到包括高度保守的Skp 2结合结构域的c-Myc区域。Skp 2已显示调节c-Myc稳定性，并且还显示作为c-Myc靶基因转录的共激活因子起作用。我们现在表明，EB病毒潜伏癌蛋白EBNA 3C可以稳定c-Myc和c-Myc及其辅因子Skp 2的募集c-Myc依赖的启动子可以增强c-Myc依赖的转录。EBNA 3C的同一区域也募集和调节视网膜母细胞瘤和p27的活性，两者都是哺乳动物细胞周期的主要调节因子。在由该结构域调节的细胞靶标组中包含c-Myc进一步强调了EBNA 3C的这些关键残基在绕过细胞周期检查点中的重要性。
Epstein-Barr virus (EBV) was the first human DNA virus to be associated with cancer. Its oncogenic potential was further demonstrated by its ability to transform primary B lymphocytes in vitro. EBV nuclear antigen 3C (EBNA3C) is one of a small subset of latent antigens critical for the transformation of human primary B lymphocytes. Although EBNA3C has been shown to modulate several cellular functions, additional targets involved in cellular transformation remain to be explored. EBNA3C can recruit key components of the SCFSkp2 ubiquitin ligase complex. In this report, we show that EBNA3C residues 130 to 190, previously shown to bind to the SCFSkP2 complex, also can strongly associate with the c-Myc oncoprotein. Additionally, the interaction of EBNA3C with c-Myc was mapped to the region of c-Myc that includes the highly conserved Skp2 binding domain. Skp2 has been shown to regulate c-Myc stability and also has been shown to function as a coactivator of transcription for c-Myc target genes. We now show that the EBV latent oncoprotein EBNA3C can stabilize c-Myc and that the recruitment of both c-Myc and its cofactor Skp2 to c-Myc-dependent promoters can enhance c-Myc-dependent transcription. This same region of EBNA3C also recruits and modulates the activity of retinoblastoma and p27, both major regulators of the mammalian cell cycle. The inclusion of c-Myc in the group of cellular targets modulated by this domain further accentuates the importance of these critical residues of EBNA3C in bypassing the cell cycle checkpoints.