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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Identification of GAPDH as a protein target of the saframycin antiproliferative agents
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Identification of GAPDH as a protein target of the saframycin antiproliferative agents

机译：鉴定GAPDH作为沙弗霉素抗增殖剂的蛋白质靶标

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摘要

Saframycin A (SafA) is a member of a class of natural products with potent antiproliferative effects in leukemia- and tumor-derived cells. This activity is frequently conjectured to derive from the ability of saframycins to covalently modify duplex DNA. We used a DNA-linked affinity purification technique to identify GAPDH as a protein target of DNA-small molecule adducts of several members of the saframycin class. Nuclear translocation of GAPDH occurs upon treatment of cancer cells with saframycins, and depletion of cellular GAPDH levels by small interfering RNA transfection confers drug resistance. Roeder and coworkers have recently suggested that GAPDH is a key transcriptional coactivator necessary for entry into S phase. Our data suggest that GAPDH is also capable of forming a ternary complex with saframycin-related compounds and DNA that induces a toxic response in cells. These studies implicate a previously unknown molecular mechanism of antiproliferative activity and, given that one member of the saframycin class has shown efficacy in cancer treatment, suggest that GAPDH may be a potential target for chemotherapeutic intervention.
机译：Saframycin A（SafA）是一类天然产物的成员，在白血病和肿瘤衍生细胞中具有有效的抗增殖作用。通常推测这种活性源自沙弗霉素共价修饰双链体DNA的能力。我们使用了一种DNA链接的亲和纯化技术，将GAPDH鉴定为沙弗霉素类几个成员的DNA小分子加合物的蛋白质靶标。 GAPDH的核易位发生在用沙霉素治疗癌细胞时，而小分子干扰RNA转染耗尽了细胞GAPDH的水平则赋予了耐药性。 Roeder及其同事最近提出，GAPDH是进入S期所必需的关键转录共激活因子。我们的数据表明，GAPDH还能够与沙曲霉素相关的化合物和DNA形成三元复合物，从而在细胞中引起毒性反应。这些研究暗示了以前未知的抗增殖活性的分子机制，并且鉴于the曲霉素类的一个成员已显示出在癌症治疗中的功效，因此表明GAPDH可能是化学疗法干预的潜在靶标。

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