Mechanism of cell entry and transformation by enzootic nasal tumor virus
Mechanism of cell entry and transformation by enzootic nasal tumor virus
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DOI：
10.1128/jvi.76.5.2141-2149.2002
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发表时间：
2002-03-01
影响因子：
5.4
通讯作者：
Miller, AD
中科院分区：
文献类型：
--
作者：
Dirks, C;Duh, FM;Miller, AD
地方性鼻肿瘤病毒（ENTV）可诱导感染绵羊的鼻上皮癌，但它是一种缺乏已知致癌基因的简单逆转录病毒。ENTV与绵羊肺腺瘤逆转录病毒（jagsiekte sheep retrovirus，JSRV）密切相关，后者也会导致绵羊的癌症，但会导致下呼吸道和肺泡的上皮细胞癌症。在这里，我们表明，与JSRV一样，ENTV的包膜（Env）蛋白可以转化培养的细胞，因此可能是动物中肿瘤发生的原因。此外，ENTV Env蛋白介导的病毒进入使用与JSRV Env（候选肿瘤抑制因子Hya12）相同的受体。然而，ENTV Env介导进入细胞的物种范围比JSRV更有限，基于这一发现，我们已经确定了Env蛋白中对病毒进入很重要的氨基酸区域。此外，由于ENTV不能有效地利用人Hya12作为受体，我们克隆了绵羊Hya12 cDNA，并显示编码的蛋白质作为ENTV和JSRV的有效受体。总之，虽然ENTV和JSRV使用相同的细胞表面受体进入细胞，并显然通过相同的机制转化细胞，但它们在感染绵羊的不同组织中诱导癌症，表明肿瘤发生在其他水平上受到调节。这些病毒中的转录调控元件非常不同，表明组织特异性肿瘤发生可能在病毒基因表达水平上受到调控。
Enzootic nasal tumor virus (ENTV) induces nasal epithelial cancer in infected sheep, but it is a simple retrovirus lacking a known oncogene. ENTV is closely related to jaagsiekte sheep retrovirus (JSRV), which also causes cancer in sheep but in the epithelial cells of the lower airways and alveoli. Here we show that as with JSRV, the envelope (Env) protein of ENTV can transform cultured cells and thus is likely to be responsible for oncogenesis in animals, In addition, the ENTV Env protein mediates virus entry using the same receptor as does JSRV Env, the candidate tumor suppressor Hya12. However, ENTV Env mediates entry into cells from a more restricted range of species than does JSRV, and based on this finding we have identified amino acid regions in the Env proteins that are important for virus entry. Also, because ENTV does not efficiently use human Hya12 as a receptor, we cloned the ovine Hya12 cDNA and show that the encoded protein functions as an efficient receptor for both ENTV and JSRV. In summary, although ENTV and JSRV use the same cell surface receptor for cell entry and apparently transform cells by the same mechanism, they induce cancer in different tissues of infected sheep, indicating that oncogenesis is regulated at some other level. The transcriptional regulatory elements in these viruses are quite different, indicating that tissue-specific oncogenesis is likely regulated at the level of viral gene expression.