Thymidylate synthase as an oncogene: A novel role for an essential DNA synthesis enzyme
Thymidylate synthase as an oncogene: A novel role for an essential DNA synthesis enzyme
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DOI：
10.1016/s1535-6108(04)00080-7
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发表时间：
2004-04-01
期刊：
影响因子：
50.3
通讯作者：
Zajac-Kaye, M
中科院分区：
文献类型：
--
作者：
Rahman, L;Voeller, D;Zajac-Kaye, M
胸苷酸合成酶（TS）是一种E2F1调节的酶，对DNA合成和修复至关重要。TS蛋白和mRNA水平在许多人类癌症中升高，并且高TS水平与结直肠癌、乳腺癌、宫颈癌、膀胱癌、肾癌和非小细胞肺癌患者的不良预后相关。在这项研究中，我们表明，异位表达的催化活性TS是足以诱导转化的表型在哺乳动物细胞表现为病灶形成，锚定独立的生长，和裸鼠肿瘤的形成。相比之下，在催化结构域内携带单点突变的两个TS突变体的相当水平没有转化活性。此外，我们表明TS的过表达会导致血清去除后细胞凋亡。这些数据表明，TS表现出癌基因样活性，并建议TS调节的DNA合成和肿瘤表型的诱导之间的联系。
Thymidylate synthase (TS) is an E2F1-regulated enzyme that is essential for DNA synthesis and repair. TS protein and mRNA levels are elevated in many human cancers, and high TS levels have been correlated with poor prognosis in patients with colorectal, breast, cervical, bladder, kidney, and non-small cell lung cancers. In this study, we show that ectopic expression of catalytically active TS is sufficient to induce a transformed phenotype in mammalian cells as manifested by foci formation, anchorage independent growth, and tumor formation in nude mice. In contrast, comparable levels of two TS mutants carrying single point mutations within the catalytic domain had no transforming activity. In addition, we show that overexpression of TS results in apoptotic cell death following serum removal. These data demonstrate that TS exhibits oncogene-like activity and suggest a link between TS-regulated DNA synthesis and the induction of a neoplastic phenotype.