Arsenic suppresses GDF1 expression via ROS-dependent downregulation of specificity protein 1

下调和上调 基因敲除 染色质免疫沉淀 亚砷酸盐 化学 砷毒性 激活剂(遗传学) 转录因子Sp1 心理压抑 活性氧 发起人 细胞生物学 生物 分子生物学 生物化学 基因表达 基因 有机化学
作者
Xiaobo Gao,Chen Zhang,Panpan Zheng,Qinghua Dan,Haiyan Luo,Xu Ma,Cailing Lu
出处
期刊:Environmental Pollution [Elsevier BV]
卷期号:271: 116302-116302 被引量:15
标识
DOI:10.1016/j.envpol.2020.116302
摘要

Inorganic arsenic, an environmental contaminant, has adverse health outcomes. Our previous studies showed that arsenic causes abnormal cardiac development in zebrafish embryos by downregulating Dvr1/GDF1 expression and that folic acid protects against these effects. However, the mechanism by which arsenic represses Dvr1/GDF1 expression remains unknown. Herein, we demonstrate that specificity protein 1 (Sp1) acts as a transcriptional activator of GDF1. Arsenic treatment downregulated Sp1 at both the mRNA and protein level and its downstream targets GDF1 and SIRT1. Chromatin immunoprecipitation analysis showed that the occupancy of Sp1 on the GDF1 or SIRT1 promoter was significantly reduced in response to arsenite. Further investigation showed that Sp1 overexpression inhibited the arsenic-mediated decrease in GDF1 and SIRT1, while Sp1 knockdown had the opposite effect. We found that expression of the oxidative adaptor p66shc was inversely related to that of SIRT1 and that the binding of SIRT1 to the p66shc promoter was sharply attenuated by arsenite treatment. SIRT1 overexpression attenuated p66shc expression but enhanced GDF1 protein expression, while SIRT1 depletion exerted the opposite effect. Both the antioxidants N-acetylcysteine and folic acid reversed the arsenic-mediated repression of Sp1, GDF1 and SIRT1. Moreover, wild-type p66shc overexpression enhanced the arsenic-mediated repression of Sp1, GDF1 and SIRT1, which was accompanied by an increase in intracellular reactive oxygen species (ROS) levels, while both overexpression of a dominant negative p66shcSer36Ala mutant and deficiency in p66shc reversed these effects. Taken together, our results revealed that arsenic suppresses GDF1 expression via the ROS-dependent downregulation of the Sp1/SIRT1 axis, which forms a negative feedback loop with p66shc to regulate oxidative stress. Our findings reveal a novel molecular mechanism underlying arsenic toxicity and provide new insight into the protective effect of folic acid in arsenic-mediated toxicity.
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