Arsenic alters the function of the glucocorticoid receptor as a transcription factor.
Arsenic alters the function of the glucocorticoid receptor as a transcription factor.
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DOI：
10.1289/ehp.01109245
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发表时间：
2001-03
影响因子：
10.4
通讯作者：
Hamilton JW
中科院分区：
文献类型：
--
作者：
Kaltreider RC;Davis AM;Lariviere JP;Hamilton JW
人类长期暴露于非明显毒性剂量的砷与癌症风险增加有关。虽然砷的致癌机制尚不清楚，但砷不会直接导致DNA损伤或突变，因此被认为主要是作为一种共诱变剂、共致癌剂和/或肿瘤促进剂。本实验室先前的研究表明，低剂量砷（III）（亚砷酸盐）对糖皮质激素调节的磷酸烯醇式丙酮酸羧激酶（PEPCK）基因表达的影响与糖皮质激素受体（GR）介导的调节途径密切相关。因此，我们专门研究了亚砷酸盐对GR的生化功能的影响，在H4 IIE大鼠肝癌细胞中的免疫反应。完全无细胞毒性的亚砷酸盐治疗（0.3-3.3 μ M）显着降低地塞米松诱导的表达的瞬时转染荧光素酶结构包含一个完整的PEPCK基因或两个串联糖皮质激素反应元件（GRE）的启动子。绿色荧光蛋白标记的GR融合蛋白的Western印迹和共聚焦显微镜显示，亚砷酸盐预处理并不能阻断正常的地塞米松诱导的GR核转位。这些数据表明，无毒剂量的亚砷酸盐可以直接与GR复合物相互作用，并选择性地抑制GR介导的转录，这与核功能改变有关，而不是与糖皮质激素诱导的GR激活或核转位减少有关。
Chronic human exposure to nonovertly toxic doses of arsenic is associated with an increased risk of cancer. Although its carcinogenic mechanism is still unknown, arsenic does not directly cause DNA damage or mutations and is therefore thought to act principally as a co-mutagen, co-carcinogen, and/or tumor promoter. Previous studies in our laboratory demonstrated that effects of low-dose arsenic (III) (arsenite) on expression of the hormone-regulated phosphoenolpyruvate carboxykinase (PEPCK) gene were strongly associated with the glucocorticoid receptor (GR)-mediated regulatory pathway. We therefore examined specifically the effects of arsenite on the biochemical function of GR in hormone-responsive H4IIE rat hepatoma cells. Completely noncytotoxic arsenite treatments (0.3-3.3 microM) significantly decreased dexamethasone-induced expression of transiently transfected luciferase constructs containing either an intact hormone-responsive promoter from the mammalian PEPCK gene or two tandem glucocorticoid response elements (GRE). Western blotting and confocal microscopy of a green fluorescent protein-tagged-GR fusion protein demonstrated that arsenite pretreatment did not block the normal dexamethasone-induced nuclear translocation of GR. These data indicate that nontoxic doses of arsenite can interact directly with GR complexes and selectively inhibit GR-mediated transcription, which is associated with altered nuclear function rather than a decrease in hormone-induced GR activation or nuclear translocation.
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影响因子：
10.4
作者：
Hamilton, JW;Kaltreider, RC;Lariviere, JP
通讯作者：
Lariviere, JP
影响因子：
1.7
作者：
DROMS, KA;MALKINSON, AM
通讯作者：
MALKINSON, AM
DOI：
10.1016/0960-0760(92)90188-o
发表时间：
1992-09-01
影响因子：
4.1
作者：
CATO, ACB;KONIG, H;HERRLICH, P
通讯作者：
HERRLICH, P
影响因子：
8.4
作者：
Hofmann, J;Kaiser, U;Havemann, K
通讯作者：
Havemann, K
DOI：
10.1083/jcb.133.5.985
发表时间：
1996-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Carey KL;Richards SA;Lounsbury KM;Macara IG
通讯作者：
Macara IG