Cell polarity proteins: common targets for tumorigenic human viruses.
Cell polarity proteins: common targets for tumorigenic human viruses.
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DOI：
10.1038/onc.2008.352
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发表时间：
2008-11-24
期刊：
影响因子：
8
通讯作者：
Javier, R. T.
中科院分区：
文献类型：
--
作者：
Javier, R. T.
细胞连接的极性丧失和破坏是上皮来源的癌细胞的共同特征，越来越多的证据表明，这种缺陷在癌症的病理学中具有直接的功能。支持这一观点的是，几种不同的人类肿瘤病毒的结果表明，它们的致癌潜力部分取决于一种共同的能力，即破坏细胞极性蛋白。例如，腺病毒（Ad）9型在人类Ad中是独特的，其在实验动物中仅引起雌激素依赖性乳腺肿瘤，并且具有E4区编码的开放阅读框1（E4-ORF 1）作为其主要致癌决定子。E4-ORF 1蛋白由两个独立的蛋白质相互作用元件组成，其中一个元件定义了E4-ORF 1诱导体外细胞转化和体内肿瘤发生所需的PDZ结构域结合基序（PBM）。最值得注意的是，E4-ORF 1 PBM介导与选定的一组细胞PDZ蛋白的相互作用，其中三种包括细胞极性蛋白Dlg 1、PATJ和ZO-2。数据进一步表明，这些相互作用促进细胞连接的破坏和细胞极性的丧失。此外，一种或多种E4-ORF 1相互作用细胞极性蛋白以及细胞极性蛋白Scribble是高危人乳头瘤病毒（HPV）E6或人T细胞白血病病毒1型（HTLV-1）Tax癌蛋白的常见靶标。强调这些观察结果的重要性，在人类中，高危HPV和HTLV-1分别是宫颈癌和成人T细胞白血病的病原体。因此，人类肿瘤病毒应该作为解释细胞连接的破坏和细胞极性的丧失导致许多人类癌症发展的机制的有力工具。这篇综述文章讨论了支持这一假设的证据，重点是人类Ad E4-ORF 1癌蛋白。
Loss of polarity and disruption of cell junctions are common features of epithelial-derived cancer cells, and mounting evidence indicates that such defects have a direct function in the pathology of cancer. Supporting this idea, results with several different human tumor viruses indicate that their oncogenic potential depends in part on a common ability to inactivate key cell polarity proteins. For example, adenovirus (Ad) type 9 is unique among human Ads by causing exclusively estrogen-dependent mammary tumors in experimental animals and in having E4 region-encoded open reading frame 1 (E4-ORF1) as its primary oncogenic determinant. The 125-residue E4-ORF1 protein consists of two separate protein-interaction elements, one of which defines a PDZ domain-binding motif (PBM) required for E4-ORF1 to induce both cellular transformation in vitro and tumorigenesis in vivo. Most notably, the E4-ORF1 PBM mediates interactions with a selected group of cellular PDZ proteins, three of which include the cell polarity proteins Dlg1, PATJ and ZO-2. Data further indicate that these interactions promote disruption of cell junctions and a loss of cell polarity. In addition, one or more of the E4-ORF1-interacting cell polarity proteins, as well as the cell polarity protein Scribble, are common targets for the high-risk human papillomavirus (HPV) E6 or human T-cell leukemia virus type 1 (HTLV-1) Tax oncoproteins. Underscoring the significance of these observations, in humans, high-risk HPV and HTLV-1 are causative agents for cervical cancer and adult T-cell leukemia, respectively. Consequently, human tumor viruses should serve as powerful tools for deciphering mechanisms whereby disruption of cell junctions and loss of cell polarity contribute to the development of many human cancers. This review article discusses evidence supporting this hypothesis, with an emphasis on the human Ad E4-ORF1 oncoprotein.
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