Involvement of PLAGL2 in activation of iron deficient- and hypoxia-induced gene expression in mouse cell lines

Oncogene. 2001 Aug 2;20(34):4718-27. doi: 10.1038/sj.onc.1204647.


We searched iron-deficient inducible cDNA, using subtraction cloning and mRNA from desferrioxamine-treated mouse macrophage Raw264.7 cells. We identified a pleomorphic adenoma gene like 2 (PLAGL2), one of PLAG superfamily proteins exhibiting antiproliferative properties on tumor cells. Mouse PLAGL2 consists of 496 amino acids with seven C2H2 zinc-fingers. PLAGL2 mRNA was induced in RAW264.7 cells, mouse erythroleukemia cells and Balb/c 3T3 cells when they were treated with desferrioxamine. Hypoxia also increased PLAGL2 mRNA. Expression of PLAGL2 in COS-7 cells led to nuclear localization. PLAGL2 had potential binding ability to GC-rich oligonucleotide and activated transcription of a gene with the binding sequence in transient reporter assay, a finding consistent with a case seen in a PLAGL2 homolog, ZAC-1. Transient co-transfection of PLAGL2 or ZAC1 cDNA and a reporter containing a lactate dehydrogenase A (LDHA) promoter carrying the hypoxia inducible factor-1 responsive element led to an increase in the basal transcription in Balb/c 3T3 and HepG2 cells. Activation in transcription from the LDHA promoter increased by desferrioxamine treatment or hypoxia was further enhanced when PLAGL2 was expressed. We propose that PLAGL2 is involved in the cell cycle arrest and apoptosis of tumor cells by regulating iron depletion- or hypoxia-inducible gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / physiology
  • Cell Hypoxia
  • Cell Line
  • Cell Nucleus / metabolism
  • Cloning, Molecular
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Deferoxamine / pharmacology
  • Genes, Tumor Suppressor*
  • Humans
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Iron / metabolism*
  • Iron Chelating Agents / pharmacology
  • Isoenzymes / genetics
  • L-Lactate Dehydrogenase / genetics
  • Lactate Dehydrogenase 5
  • Mice
  • Molecular Sequence Data
  • Nuclear Proteins / genetics
  • Promoter Regions, Genetic
  • RNA, Messenger / biosynthesis
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / physiology*
  • Response Elements
  • Sequence Homology, Amino Acid
  • Trans-Activators / genetics
  • Trans-Activators / physiology
  • Transcription Factors*
  • Transcriptional Activation
  • Tumor Suppressor Proteins


  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Iron Chelating Agents
  • Isoenzymes
  • Nuclear Proteins
  • PLAGL1 protein, human
  • PLAGL2 protein, human
  • Plagl1 protein, mouse
  • Plagl2 protein, mouse
  • RNA, Messenger
  • RNA-Binding Proteins
  • Trans-Activators
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Iron
  • L-Lactate Dehydrogenase
  • Lactate Dehydrogenase 5
  • Deferoxamine

Associated data

  • GENBANK/AB051854