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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >T Antigen Mutations Are A Human Tumor-specific Signature For Merkel Cell Polyomavirus
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T Antigen Mutations Are A Human Tumor-specific Signature For Merkel Cell Polyomavirus

机译：T抗原突变是默克尔细胞多瘤病毒的人类肿瘤特异性特征。

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Merkel cell polyomavirus (MCV) is a virus discovered in our laboratory at the University of Pittsburgh that is monoclonally integrated into the genome of ≈80% of human Merkel cell carcinomas (MCCs). Transcript mapping was performed to show that MCV expresses transcripts in MCCs similar to large T (LT), small T (ST), and 17kT transcripts of SV40. Nine MCC tumor-derived LT genomic sequences have been examined, and all were found to harbor mutations prematurely truncating the MCV LT helicase. In contrast, four presumed episomal viruses from nontumor sources did not possess this T antigen signature mutation. Using coimmunopre-cipitation and origin replication assays, we show that tumor-derived virus mutations do not affect retinoblastoma tumor suppressor protein (Rb) binding by LT but do eliminate viral DNA replication capacity. Identification of an MCC cell line (MKL-1) having monoclonal MCV integration and the signature LT mutation allowed us to functionally test both tumor-derived and wild type (WT) T antigens. Only WT LT expression activates replication of integrated MCV DNA in MKL-1 cells. Our findings suggest that MCV-positive MCC tumor cells undergo selection for LT mutations to prevent autoactivation of integrated virus replication that would be detrimental to cell survival. Because these mutations render the virus replication-incompetent, MCV is not a "passenger virus" that secondarily infects MCC tumors.
机译：默克尔细胞多瘤病毒（MCV）是在匹兹堡大学实验室中发现的一种病毒，它被单克隆整合到约80％的人类默克尔细胞癌（MCC）的基因组中。进行转录本作图以显示MCV在MCC中表达转录本，类似于SV40的大T（LT），小T（ST）和17kT转录本。已经检查了九种MCC肿瘤来源的LT基因组序列，发现所有这些基因组都具有过早截断MCV LT解旋酶的突变。相反，来自非肿瘤来源的四种推测的游离病毒不具有该T抗原签名突变。使用共免疫沉淀和起源复制测定法，我们表明肿瘤来源的病毒突变不会影响LT结合成视网膜细胞瘤抑癌蛋白（Rb），但会消除病毒DNA复制能力。具有单克隆MCV整合和标志性LT突变的MCC细胞系（MKL-1）的鉴定使我们能够在功能上测试肿瘤来源的T抗原和野生型（WT）T抗原。仅WT LT表达激活MKL-1细胞中整合的MCV DNA的复制。我们的发现表明，MCV阳性的MCC肿瘤细胞经过LT突变选择，以防止整合病毒复制的自动激活，这会损害细胞存活率。由于这些突变使病毒无法复制，因此MCV并不是继发感染MCC肿瘤的“客体病毒”。

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