Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator
Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator
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DOI：
10.1172/jci46323
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发表时间：
2011-09-01
影响因子：
15.9
通讯作者：
Moore, Patrick S.
中科院分区：
文献类型：
--
作者：
Shuda, Masahiro;Kwun, Hyun Jin;Moore, Patrick S.
默克尔细胞多瘤病毒(MCV)是最近发现的大多数默克尔细胞癌(MCC)的原因，MCC是一种侵袭性的非黑色素瘤皮肤癌。虽然已知MCV整合到肿瘤细胞基因组中并发生突变，但这种病毒用于致癌的分子机制尚不清楚。在这里，我们发现MCV小T(ST)抗原在大多数MCC肿瘤中都有表达，这是肿瘤细胞生长所必需的。与密切相关的SV40ST不同，MCV ST将啮齿动物成纤维细胞转化为锚定和接触无关的生长，并促进了人细胞的无血清增殖。这些作用不涉及蛋白磷酸酶2A(PP2A)的抑制。研究发现，MCV ST作用于哺乳动物雷帕霉素靶标(MTOR)信号通路下游，保护真核细胞翻译起始因子4E结合蛋白1(4E-BP1)的过度磷酸化，导致帽依赖翻译的失调。MCV ST相关的4E-BP1丝氨酸65过度磷酸化对mTOR复合体(MTORC1)和mTORC2抑制剂耐药。MCV ST还促进了其他Akt-mTOR下游靶基因的稳态磷酸化，包括S6K和4E-BP2。不能磷酸化的4E-BP1的表达可拮抗MCV-ST的细胞转化活性。综上所述，这些实验表明，MCV转化需要抑制4E-BP1。因此，MCV-ST是一种癌蛋白，其在调控异常的帽依赖翻译中的作用对MCV相关癌症的预防、诊断和治疗具有临床意义。
Merkel cell polyomavirus (MCV) is the recently discovered cause of most Merkel cell carcinomas (MCCs), an aggressive form of nonmelanoma skin cancer. Although MCV is known to integrate into the tumor cell genome and to undergo mutation, the molecular mechanisms used by this virus to cause cancer are unknown. Here, we show that MCV small T (sT) antigen is expressed in most MCC tumors, where it is required for tumor cell growth. Unlike the closely related SV40 sT, MCV sT transformed rodent fibroblasts to anchorageand contact-independent growth and promoted serum-free proliferation of human cells. These effects did not involve protein phosphatase 2A (PP2A) inhibition. MCV sT was found to act downstream in the mammalian target of rapamycin (mTOR) signaling pathway to preserve eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) hyperphosphorylation, resulting in dysregulated cap-dependent translation. MCV sT-associated 4E-BP1 serine 65 hyperphosphorylation was resistant to mTOR complex (mTORC1) and mTORC2 inhibitors. Steady-state phosphorylation of other downstream Akt-mTOR targets, including S6K and 4E-BP2, was also increased by MCV sT. Expression of a constitutively active 4E-BP1 that could not be phosphorylated antagonized the cell transformation activity of MCV sT. Taken together, these experiments showed that 4E-BP1 inhibition is required for MCV transformation. Thus, MCV sT is an oncoprotein, and its effects on dysregulated cap-dependent translation have clinical implications for the prevention, diagnosis, and treatment of MCV-related cancers.