Down-Regulation of the Expression of the FIH-1 and ARD-1 Genes at the Transcriptional Level by Nickel and Cobalt in the Human Lung Adenocarcinoma A549 Cell Line

International Journal of Environmental Research and Public Health

Qingdong Ke¹  Thomas Kluz¹ 

[1] Nelson Institute of Environmental Medicine, New York University, School of Medicine, 57 Old Forge Road, Tuxedo, New York 10987, USA

关键词: nickel;    cobalt;    hypoxia;    HIF-1a;    FIH-1;    ARD-1;   

DOI  :  10.3390/ijerph2005010010

来源: mdpi

【 摘 要 】

Although nickel and cobalt compounds have been known to cause induction of the transcription factor hypoxia-inducible factor 1 (HIF-1) and activation of a battery of hypoxia-inducible genes in the cell, the molecular mechanisms of this induction remain unclear. The post-translational modification of HIF-1a, the oxygen-sensitive subunit of HIF-1, regulates stabilization, nuclear translocation, DNA binding activity, and transcriptional activity of the protein. Among the enzymes regulating the post-translational modification of HIF-1a, the factor inhibiting HIF-1 (FIH-1) hydroxylates the protein at asparagine 803, suppressing the interaction of HIF-1a with transcription coactivators p300/CBP and reducing the transcriptional activity of the protein. ARD-1, the acetyltransferase, acetylates HIF-1a at lysine 532, which enhances the interaction of HIF-1a with pVHL. Therefore, FIH-1 and ARD-1 negatively regulate the transcriptional activity and the stability of HIF-1a. We examined the mRNA levels of FIH-1 and ARD-1 genes after exposure nickel (II) or cobalt (II) to the cell and found that both genes were down-regulated by the chemical treatment, which may lead to reduced levels of both proteins and result in increased level of HIF-1a and its transcriptional activity.

【 授权许可】

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