Molecular basis for effects of carcinogenic heavy metals on inducible gene expression
Molecular basis for effects of carcinogenic heavy metals on inducible gene expression
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DOI：
10.2307/3434145
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发表时间：
1998-08-01
影响因子：
10.4
通讯作者：
Lariviere, JP
中科院分区：
文献类型：
--
作者：
Hamilton, JW;Kaltreider, RC;Lariviere, JP
某些形式的重金属砷和铬被认为是人类致癌物，尽管人们认为它们通过非常不同的机制发挥作用。铬 (VI) 被认为是一种典型的基因毒性和诱变剂，而 DNA/染色质似乎是其作用的主要目标。相比之下，砷 (III) 被认为是无基因毒性的，但能够主要通过巯基相互作用靶向特定的细胞蛋白质。我们之前已经证明，包括六价铬在内的各种遗传毒性化学致癌物会优先改变几种诱导基因的表达，但对组成型基因表达影响很小或没有影响。因此，我们感兴趣的是这些致癌重金属是否可能针对细胞内特定但不同的位点，导致基因表达的改变，从而可能促进致癌过程。在体内鸡胚和培养的大鼠肝癌 H4IIE 细胞中，砷 (III) 和铬 (VI) 在非明显毒性剂量下均显着改变模型诱导基因磷酸烯醇丙酮酸羧激酶 (PEPCK) 的基础表达和激素诱导表达。我们最近开发了两种平行的细胞培养方法来检查这些效应的分子基础。首先，我们正在研究重金属对已知参与易感诱导基因调节的特定转录因子的表达和激活的影响，并且最近观察到砷（III）和铬（VI）对核转录因子结合的显着但不同的影响。其次，我们开发了具有稳定整合的PEPCK启动子-荧光素酶报告基因构建体的细胞系，以检查重金属对启动子功能的影响，并且最近还发现了铬（VI）和砷（III）在该系统中诱导的深远影响。这些模型系统应该使我们能够识别重金属暴露导致特定易感基因表达改变的关键顺式（DNA）和反式（蛋白质）细胞靶标。预计这些信息将为了解这些影响的机制基础提供有价值的见解，并为评估人类暴露提供敏感的分子生物标志物。
Certain forms of the heavy metals arsenic and chromium are considered human carcinogens, although they are believed to act through very different mechanisms. Chromium(VI) is believed to act as a classic genotoxic and mutagenic agent, and DNA/chromatin appears to be the principal target for its effects. In contrast, arsenic(III) is considered nongenotoxic, but is able to target specific cellular proteins, principally through sulfhydryl interactions. We had previously shown that various genotoxic chemical carcinogens, including chromium(VI), preferentially altered expression of several inducible genes but had little or no effect on constitutive gene expression. We were therefore interested in whether these carcinogenic heavy metals might target specific but distinct sites within cells, leading to alterations in gene expression that might contribute to the carcinogenic process. Arsenic(III) and chromium(VI) each significantly altered both basal and hormone-inducible expression of a model inducible gene, phosphoenolpyruvate carboxykinase (PEPCK), at nonovertly toxic doses in the chick embryo in vivo and rat hepatoma H4IIE cells in culture. We have recently developed two parallel cell culture approaches for examining the molecular basis for these effects. First, we are examining the effects of heavy metals on expression and activation of specific transcription factors known to be involved in regulation of susceptible inducible genes, and have recently observed significant but different effects of arsenic(III) and chromium(Vl) on nuclear transcription factor binding. Second, we have developed cell lines with stably integrated PEPCK promoter-luciferase reporter gene constructs to examine effects of heavy metals on promoter function, and have also recently seen profound effects induced by both chromium(VI) and arsenic(III) in this system. These model systems should enable us to be able to identify the critical cis (DNA) and trans (protein) cellular targets of heavy metal exposure leading to alterations in expression of specific susceptible genes. It is anticipated that such information will provide valuable insight into the mechanistic basis for these effects as well as provide sensitive molecular biomarkers for evaluating human exposure.