Transgenic expression of human thymidylate synthase accelerates the development of hyperplasia and tumors in the endocrine pancreas
Transgenic expression of human thymidylate synthase accelerates the development of hyperplasia and tumors in the endocrine pancreas
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DOI：
10.1038/sj.onc.1210273
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发表时间：
2007-07-19
期刊：
影响因子：
8
通讯作者：
Zajac-Kaye, M.
中科院分区：
文献类型：
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作者：
Chen, M.;Rahman, L.;Zajac-Kaye, M.
胸苷酸合酶 (TS) 是 DNA 合成和修复的必需酶，TS 水平升高已被确定为结直肠癌和其他几种常见人类恶性肿瘤的重要预后生物标志物。此外，通过视网膜母细胞瘤蛋白抑制 TS 等 E2F 靶基因转录激活的能力，TS 基因表达与细胞周期调节和细胞增殖相关。因此，TS 的过量产生可能参与肿瘤表型的进展。与该模型一致的是，最近的一项研究表明，异位 TS 表达可以诱导哺乳动物细胞表型的转变。为了研究失调的 TS 活性在肿瘤发展中的作用，我们培育了转基因小鼠，这些小鼠仅在胰腺中表达高水平的催化活性人类 TS（hTS），而在多个其他组织中表达低水平的 hTS。对 TS 转基因小鼠胰腺组织的分析揭示了胰腺内分泌异常，从胰岛增生到胰岛细胞肿瘤的检测。 hTS 在小鼠胰岛中的过度表达提供了一种新模型来研究与从正常细胞到增生再到胰岛细胞肿瘤的进展相关的遗传改变，并表明该小鼠模型可能有助于调节体内 TS 活性，以开发癌症预防和新疗法。
Thymidylate synthase ( TS) is an essential enzyme for DNA synthesis and repair and elevated levels of TS have been identified as an important prognostic biomarker for colorectal cancer and several other common human malignancies. In addition, TS gene expression has been linked with cell-cycle regulation and cell proliferation through the ability of retinoblastoma protein to repress the transcriptional activation of E2F target genes such as TS. Therefore, overproduction of TS could participate in the progression to a neoplastic phenotype. Consistent with this model, a recent study has suggested that ectopic TS express ion can induce a transformed phenotype in mammalian cells. To investigate the role of deregulated TS activity in tumor development, we generated transgenic mice that express high levels of catalytically active human TS( hTS) exclusively in the pancreas and low levels of hTS in multiple other tissues. Analyses of pancreatic tissue in TS transgenic mice revealed abnormalities within the endocrine pancreas, ranging from pancreatic islet hyperplasia to the detection of islet cell tumors. Overexpression of hTS in murine islets provides a new model to study genetic alterations associated with the progression from normal cells to hyperplasia to islet cell tumors, and suggests that this mouse model may be useful for regulating TS activity in vivo for development of cancer prevention and new therapies.