Searching for novel ATF4 target genes in human hepatoma cells by microarray analysis

Biosci Biotechnol Biochem. 2016 Jun;80(6):1149-54. doi: 10.1080/09168451.2016.1146072. Epub 2016 Mar 11.


Activating transcription factor 4 (ATF4) is a transcription factor with an important biological activity. ATF4 is induced by various stresses, such as endoplasmic reticulum stress, through the phosphorylation of eukaryotic translation initiation factor 2α. ATF4 is also involved in lipid metabolism. In the present study, we performed a microarray experiment to identify new ATF4 target genes, particularly those involved in lipid metabolism, and identified C12orf39, CSTA, and CALCB as novel ATF4 target genes. An amino acid response element (AARE) as an ATF4-binding site is present in the promoter regions of these genes. In a detailed analysis using luciferase assay, we showed that ATF4 activated C12orf39 promoter activity and that this activation was diminished by deletion or mutation of the AARE sequence in the promoter region. Our results suggest that C12orf39, CSTA, and CALCB are novel ATF4 target genes and that C12orf39 promoter activity is activated by ATF4 through AARE.

Keywords: activating transcription factor 4(ATF4); endoplasmic reticulum stress (ER stress); microarray.

MeSH terms

  • Activating Transcription Factor 4 / genetics*
  • Activating Transcription Factor 4 / metabolism
  • Binding Sites
  • Calcitonin Gene-Related Peptide / genetics*
  • Calcitonin Gene-Related Peptide / metabolism
  • Cell Line, Tumor
  • Cystatin A / genetics*
  • Cystatin A / metabolism
  • Eukaryotic Initiation Factor-2 / genetics
  • Eukaryotic Initiation Factor-2 / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Genes, Reporter
  • Hepatocytes / metabolism*
  • Hepatocytes / pathology
  • Humans
  • Lipid Metabolism / genetics
  • Luciferases / genetics
  • Luciferases / metabolism
  • Microarray Analysis
  • Mutation
  • Peptide Hormones / genetics*
  • Peptide Hormones / metabolism
  • Protein Binding
  • Response Elements
  • Signal Transduction


  • ATF4 protein, human
  • Cystatin A
  • Eukaryotic Initiation Factor-2
  • Peptide Hormones
  • SPX protein, human
  • Activating Transcription Factor 4
  • CSTA protein, human
  • Luciferases
  • Calcitonin Gene-Related Peptide