Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase
Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase
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DOI：
10.1073/pnas.0505605102
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发表时间：
2005-12-13
影响因子：
11.1
通讯作者：
Lemon, SM
中科院分区：
文献类型：
--
作者：
Munakata, T;Nakamura, M;Lemon, SM
视网膜母细胞瘤肿瘤抑制蛋白（Rb）通过调节E2 F转录因子在控制细胞增殖和凋亡中起关键作用。Rb是由DNA肿瘤病毒表达的癌蛋白的关键靶标，但RNA病毒不知道调节Rb功能。在这里，我们表明，Rb丰度是负调控的细胞含有复制基因组RNA的丙型肝炎病毒，人类病毒与肝细胞癌密切相关。病毒RNA依赖性RNA聚合酶NS 5 B与Rb形成复合物，靶向其降解并导致Rb丰度降低、E2 F应答启动子激活和细胞增殖。NS 5 B含有一个保守的Leu-x-Cys/Asn-x-Asp基序，与DNA病毒癌蛋白中的Rb结合结构域同源。该结构域与聚合酶活性位点重叠，并且其中的突变废除Rb结合并逆转NS 5 B对E2 F启动子激活和细胞增殖的影响。这些发现表明，在肝癌发展中涉及的致癌RNA病毒和一种至关重要的肿瘤抑制蛋白之间存在独特的联系。
The retinoblastoma tumor-suppressor protein (Rb) plays a critical role in controlling cellular proliferation and apoptosis by regulating E2F transcription factors. Rb is a key target of oncoproteins expressed by DNA tumor viruses, but RNA viruses are not known to regulate Rb function. Here, we show that Rb abundance is negatively regulated in cells containing replicating genomic RNA from hepatitis C virus, a human virus strongly associated with hepatocellular carcinoma. The viral RNA-dependent RNA polymerase NS5B forms a complex with Rb,targeting it for degradation and resulting in reduction of Rb abundance, activation of E2F-responsive promoters, and cell proliferation. NS5B contains a conserved Leu-x-Cys/Asn-x-Asp motif that is, homologous to Rb-binding domains in the oncoproteins of DNA viruses. This domain overlaps the polymerase active site, and mutations within it abrogate Rb binding and reverse the effects of NS5B on E2F promoter activation and cell proliferation. These findings suggest a unique link between an oncogenic RNA virus implicated in the development of liver cancer and a critically important tumor-suppressor protein.