title: 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.
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-la, 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-l 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-1 a and its transcriptional activity.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University, School of Medicine, 57 Old Forge Road, Tuxedo, New York 10987, USA.
authors.forename: Qingdong
authors.initials: Q
authors.lastname: Ke
authors.forename: Thomas
authors.initials: T
authors.lastname: Kluz
authors.forename: Max
authors.initials: M
authors.lastname: Costa
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000230:Adenocarcinoma; D045744:Cell Line, Tumor; D003035:Cobalt / Q000633:toxicity*; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008175:Lung Neoplasms; D006899:Mixed Function Oxygenases; D063209:N-Terminal Acetyltransferase A; D063213:N-Terminal Acetyltransferase E; D009532:Nickel / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D003035:Cobalt; D009532:Nickel; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human; D000123:Acetyltransferases; D063209:N-Terminal Acetyltransferase A; C504824:NAA10 protein, human; D063213:N-Terminal Acetyltransferase E