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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

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  • Qingdong Ke

    (Nelson Institute of Environmental Medicine, New York University, School of Medicine, 57 Old Forge Road, Tuxedo, New York 10987, USA)

  • Thomas Kluz

    (Nelson Institute of Environmental Medicine, New York University, School of Medicine, 57 Old Forge Road, Tuxedo, New York 10987, USA)

  • Max Costa

    (Nelson Institute of Environmental Medicine, New York University, School of Medicine, 57 Old Forge Road, Tuxedo, New York 10987, USA)

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.

Suggested Citation

  • Qingdong Ke & Thomas Kluz & Max Costa, 2005. "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," IJERPH, MDPI, vol. 2(1), pages 1-4, April.
  • Handle: RePEc:gam:jijerp:v:2:y:2005:i:1:p:10-13:d:2706
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    References listed on IDEAS

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    1. Patrick H. Maxwell & Michael S. Wiesener & Gin-Wen Chang & Steven C. Clifford & Emma C. Vaux & Matthew E. Cockman & Charles C. Wykoff & Christopher W. Pugh & Eamonn R. Maher & Peter J. Ratcliffe, 1999. "The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis," Nature, Nature, vol. 399(6733), pages 271-275, May.
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    Keywords

    nickel; cobalt; hypoxia; HIF-1a; FIH-1; ARD-1;
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