文章：

人乳头瘤病毒癌蛋白：转化途径

Human papillomavirus oncoproteins: pathways to transformation

原文发布日期：2010-07-01

DOI: 10.1038/nrc2886

类型: Review Article

开放获取: 否

要点：

1. Human papillomaviruses (HPVs) are the causative agents of over 99% of cervical cancers. Cervical cancer is the second largest cause of cancer deaths in women worldwide.
2. Infection by high-risk HPV types is necessary but not sufficient for progression to cancer. Mutations in cellular genes and chromosomal rearrangements induced by genomic instabilities are important contributing events.
3. HPV E6 and E7 are the primary transforming viral proteins and E5 enhances proliferation and may contribute to cancer progression.
4. A primary target of E7 is the retinoblastoma (Rb) family of proteins that control the activity of E2F transcription factors, which are key regulators of S phase genes. Inactivation of Rb is important for the differentiation-dependent productive viral lifecycle and for tumour progression.
5. The efficient abrogation of Rb function by E7 leads to increased levels of p53 and, consequently, the E6 proteins have evolved to target p53 for degradation. E6 also activates telomerase expression and modulates the activities of PDZ domain-containing proteins and tumour necrosis factor receptors.
6. E7 proteins also alter cell cycle control through interactions with histone deacetylases, cyclins and cyclin-dependent kinase inhibitors.
7. E6 and E7 induce genomic instability through multiple mechanisms, including aberrant centrosome duplication.
8. E6 and E7 also target cytokine expression to modulate cell proliferation and interferon responses, contributing to immune evasion.
9. E5 binds to B cell receptor-associated protein 31 in the endoplasmic reticulum to control trafficking of proteins and to the vacuolar ATPase in endosomes to modulate epidermal growth factor receptor turnover and maintain constitutive signalling.

要点翻译：

1. 人乳头瘤病毒（HPV）是超过99%宫颈癌的致病源。宫颈癌是全球女性癌症死亡的第二大原因。
2. 高危型HPV感染是进展为癌症的必要条件，但并非充分条件。细胞基因突变和基因组不稳定性诱导的染色体重排是重要的促成因素。
3. HPV E6和E7是主要的病毒转化蛋白，E5则能增强增殖能力并可能促进癌症进展。
4. E7的主要作用靶点是视网膜母细胞瘤（Rb）蛋白家族，这些蛋白控制着S期基因关键调控因子E2F转录因子的活性。Rb蛋白的失活对于分化依赖性病毒复制周期和肿瘤进展至关重要。
5. E7有效破坏Rb功能会导致p53水平升高，因此E6蛋白进化出靶向降解p53的功能。E6还能激活端粒酶表达，并调节含PDZ结构域蛋白和肿瘤坏死因子受体的活性。
6. E7蛋白还通过组蛋白去乙酰化酶、细胞周期蛋白及细胞周期蛋白依赖性激酶抑制因子的相互作用改变细胞周期调控。
7. E6和E7通过多种机制诱导基因组不稳定性，包括异常中心体复制。
8. E6和E7还靶向细胞因子表达以调节细胞增殖和干扰素反应，从而促进免疫逃逸。
9. E5与内质网中的B细胞受体相关蛋白31结合以调控蛋白运输，并与内体中的液泡ATP酶结合以调节表皮生长因子受体周转，维持持续性信号传导。

英文摘要：

An association between human papillomavirus (HPV) infection and the development of cervical cancer was initially reported over 30 years ago, and today there is overwhelming evidence that certain subtypes of HPV are the causative agents of these malignancies. The p53 and retinoblastoma proteins are well-characterized targets of the HPV E6 and E7 oncoproteins, but recent studies have shown that the alteration of additional pathways are equally important for transformation. These additional factors are crucial regulators of cell cycle progression, telomere maintenance, apoptosis and chromosomal stability. Understanding how HPV oncoproteins modify these activities provides novel insights into the basic mechanisms of oncogenesis.

摘要翻译： 

30多年前，人们首次报道了人乳头瘤病毒（HPV）感染与宫颈癌发生之间的关联；如今，已有大量证据表明，某些HPV亚型是这些恶性肿瘤的致病因子。p53和视网膜母细胞瘤蛋白是HPV E6和E7癌蛋白明确的作用靶点，但近期研究显示，其他通路的改变对细胞转化同样至关重要。这些额外因素调控着细胞周期进程、端粒维持、凋亡及染色体稳定性。深入了解HPV癌蛋白如何调控这些过程，可为揭示肿瘤发生的基本机制提供新的见解。

原文链接：

Human papillomavirus oncoproteins: pathways to transformation