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Int. J. Environ. Res. Public Health 2005, 2(1), 10-13; doi:10.3390/ijerph2005010010
Article

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

,  and *
Nelson Institute of Environmental Medicine, New York University, School of Medicine, 57 Old Forge Road, Tuxedo, New York 10987, USA
* Author to whom correspondence should be addressed.
Received: 15 November 2004 / Accepted: 6 February 2005 / Published: 30 April 2005
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Abstract

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.
Keywords: nickel; cobalt; hypoxia; HIF-1a; FIH-1; ARD-1 nickel; cobalt; hypoxia; HIF-1a; FIH-1; ARD-1
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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Ke, Q.; Kluz, T.; Costa, M. 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. Int. J. Environ. Res. Public Health 2005, 2, 10-13.

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