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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Inhibition of AP-1 binding and transcription by gold and selenium involving conserved cysteine residues in Jun and Fos.
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Inhibition of AP-1 binding and transcription by gold and selenium involving conserved cysteine residues in Jun and Fos.

机译：金和硒抑制Jun和Fos中保守的半胱氨酸残基对AP-1的结合和转录的抑制作用。

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摘要

Gold(I) salts and selenite, which have diverse therapeutic and biological effects, are noted for their reactivity with thiols. Since the binding of Jun-Jun and Jun-Fos dimers to the AP-1 DNA binding site is regulated in vitro by a redox process involving conserved cysteine residues, we hypothesized that some of the biological actions of gold and selenium are mediated via these residues. In electrophoretic mobility-shift analyses, AP-1 DNA binding was inhibited by gold(I) thiolates and selenite, with 50% inhibition occurring at approximately 5 microM and 1 microM, respectively. Thiomalic acid had no effect in the absence of gold(I), and other metal ions inhibited at higher concentrations, in a rank order correlating with their thiol binding affinities. Cysteine-to-serine mutants demonstrated that these effects of gold(I) and selenite require Cys272 and Cys154 in the DNA-binding domains of Jun and Fos, respectively. Gold(I) thiolates and selenite did not inhibit nonspecific protein binding to the AP-1 site and were at least an order of magnitude less potent as inhibitors of sequence-specific binding to the AP-2, TFIID, or NF1 sites compared with the AP-1 site. In addition, 10 microM gold(I) or 10 microM selenite inhibited expression of an AP-1-dependent reporter gene, but not an AP-2-dependent reporter gene. These data suggest a mechanism regulating transcription factor activity by inorganic ions which may contribute to the known antiarthritic action of gold and cancer chemoprevention by selenium.
机译：具有多种治疗和生物学作用的金（I）盐和亚硒酸盐因与硫醇的反应性而闻名。由于Jun-Jun和Jun-Fos二聚体与AP-1 DNA结合位点的结合在体外是通过涉及保守的半胱氨酸残基的氧化还原过程来调节的，因此我们假设金和硒的某些生物学作用是通过这些残基介导的。在电泳迁移率变动分析中，硫醇金（I）和亚硒酸盐抑制了AP-1 DNA的结合，分别在约5 microM和1 microM处抑制了50％。在没有金（I）的情况下，硫代马来酸没有作用，其他金属离子在较高浓度下也受到抑制，其排列顺序与其硫醇结合亲和力相关。半胱氨酸到丝氨酸突变体表明，金（I）和亚硒酸盐的这些作用分别需要在Jun和Fos的DNA结合域中使用Cys272和Cys154。金（I）硫醇盐和亚硒酸盐不抑制非特异性蛋白质与AP-1位点的结合，并且与AP-2，TFIID或NF1位点的序列特异性结合的抑制剂相比，抑制作用至少低一个数量级。 AP-1网站。此外，10 microM gold（I）或10 microM亚硒酸盐抑制AP-1依赖的报告基因的表达，但不能抑制AP-2依赖的报告基因的表达。这些数据表明了一种通过无机离子调节转录因子活性的机制，该机制可能有助于金的已知抗关节炎作用以及硒对癌症的化学预防。

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