Arsenite increases Cyclin D1 expression through coordinated regulation of the Ca2+/NFAT2 and NF-κB pathways via ERK/MAPK in a human uroepithelial cell line,Metallomics

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Arsenite increases Cyclin D1 expression through coordinated regulation of the Ca2+/NFAT2 and NF-κB pathways via ERK/MAPK in a human uroepithelial cell line
Metallomics ( IF 2.9 ) Pub Date : 2018-02-23 00:00:00 , DOI: 10.1039/c7mt00305f
Jieyu Liu _{1,

2,

3,

4,

5} , Peiyu Jin _{1,

2,

3,

4,

5} , Xiaoli Lin _{1,

2,

3,

4,

5} , Qing Zhou _{1,

2,

3,

4,

5} , Fei Wang _{1,

2,

3,

4,

5} , Shengnan Liu _{1,

2,

3,

4,

5} , Shuhua Xi _{1,

2,

3,

4,

5}

Affiliation

To understand the direct link between Cyclin D1, and nuclear factor of activated T cells 2 (NFAT2) and nuclear factor (NF)-κB in arsenic-treated bladder cells, as well as the association between MAPK and NFAT signaling, we determined whether or not the Ca²⁺/NFAT pathway is activated in an arsenic-treated normal urothelial cell line and determined the roles of NFAT and NF-κB signals in the regulation of Cyclin D1 expression. The SV-40 immortalized human uroepithelial cell line, SV-HUC-1, was treated with NaAsO₂ for 24 h (0, 1, 2, 4, 8, and 10 μM) and 10, 20, 30, and 40 weeks (0 and 0.5 μM). We found that arsenite increased the intracellular Ca²⁺ levels and induced NFAT2 nuclear translocation after treatment for 24 h. The level of NFAT2 mRNA and expression of total protein and nuclear protein were increased after long-term treatment with 0.5 μM arsenite for 30 and 40 weeks compared to the cells treated for 24 h. In addition, NF-κB p50 and p65 nuclear protein expression increased significantly in cells treated with 2–8 μM arsenite for 24 h, which was consistent with NFAT2 nuclear expression. Furthermore, an ERK inhibitor (U0126) significantly reduced the expression of NFAT2 nuclear protein, and an ERK and JNK inhibitor decreased the levels of p65 and p50 nuclear protein. Cyclin D1 is known as a proto-oncogene and the level of this protein was increased in SV-HUC-1 cells treated with arsenite for 24 h and long-term. An NFAT inhibitor (CsA) and NF-κB inhibitor (PDTC) all markedly reduced Cyclin D1 protein expression. Treatment with U0126 also significantly decreased Cyclin D1 protein expression while JNK and p38 inhibitors did not attenuate the arsenite-associated increase in Cyclin D1 protein expression. The results suggest that regulation of Cyclin D1 protein expression by arsenite in SV-HUC-1 cells is dependent on ERK/NFAT2 and ERK/NF-κB, but is not dependent on JNK or p38.

中文翻译：

亚砷酸盐通过人尿道上皮细胞系中经由ERK / MAPK 的Ca ²⁺ / NFAT2和NF-κB途径的协同调节来增加Cyclin D1的表达

为了了解细胞周期蛋白D1与砷处理过的膀胱细胞中活化T细胞2的核因子（NFAT2）和核因子（NF）-κB之间的直接联系，以及MAPK和NFAT信号之间的关联，我们确定是否Ca ²⁺ / NFAT通路在砷处理的正常尿道上皮细胞系中未被激活，并确定了NFAT和NF-κB信号在细胞周期蛋白D1表达调控中的作用。SV-40永生化人尿道上皮细胞系SV-HUC-1用NaAsO ₂处理24小时（0、1、2、4、8和10μM）和10、20、30和40周（ 0和0.5μM）。我们发现亚砷酸盐增加了细胞内Ca ²⁺治疗24小时后的血脂水平和诱导的NFAT2核易位。与处理24小时的细胞相比，用0.5μM亚砷酸盐长期处理30和40周后，NFAT2 mRNA的水平以及总蛋白和核蛋白的表达均增加。此外，在用2–8μM亚砷酸盐处理24小时的细胞中，NF-κBp50和p65核蛋白的表达显着增加，这与NFAT2核表达一致。此外，ERK抑制剂（U0126）显着降低了NFAT2核蛋白的表达，而ERK和JNK抑制剂则降低了p65和p50核蛋白的水平。细胞周期蛋白D1被称为原癌基因，长期用砷处理的SV-HUC-1细胞中该蛋白的水平增加。NFAT抑制剂（CsA）和NF-κB抑制剂（PDTC）均显着降低Cyclin D1蛋白的表达。用U0126进行的处理还显着降低了Cyclin D1蛋白的表达，而JNK和p38抑制剂并未减弱与砷有关的Cyclin D1蛋白表达的增加。结果表明，亚砷酸盐对SV-HUC-1细胞中Cyclin D1蛋白表达的调节依赖于ERK / NFAT2和ERK /NF-κB，但不依赖于JNK或p38。

更新日期：2018-02-23

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