Regulation of Gadd45gamma expression by C/EBP

Eur J Biochem. 2000 Oct;267(20):6180-7. doi: 10.1046/j.1432-1327.2000.01692.x.


The Gadd45gamma (growth arrest and DNA damage-inducible) gene is activated transcriptionally by at least two kinds of agents: DNA damaging agent such as methyl methanesulfonate (MMS) and UV radiation, or cytokines such as interleukin (IL)-6, IL-2 and granulocyte colony-stimulating factor (G-CSF). To investigate the sequences and transcription factors involved in induction of Gadd45gamma after treatment with IL-6, the human gene was cloned and sequenced. We found C/EBP (CCAAT/enhancer-binding protein) family proteins, major transcription factors in the IL-6 signal transduction pathway, could regulate the transcriptional activity of the Gadd45gamma promoter. In addition, a noncanonical C/EBP-binding site within the Gadd45gamma promoter where C/EBPbeta and C/EBPdelta could bind, was identified by electrophoretic mobility shift assay (EMSA) and reporter gene analysis. Furthermore, we found a coordinated expression profile between Gadd45gamma mRNA and C/EBPs (beta and delta) protein during the differentiation of M1 cells: the amount of Gadd45gamma transcripts became maximal when both C/EBPbeta and C/EBPdelta levels were high, on day 1 of differentiation of M1 cells after treatment with IL-6. These findings suggest that mitotic growth arrest coupled to M1 cell differentiation is mediated by C/EBPs stimulation of growth arrest-associated genes such as Gadd45gamma.

MeSH terms

  • 3T3 Cells
  • Animals
  • Base Sequence
  • Binding Sites
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Cloning, Molecular
  • DNA Damage
  • Gene Expression Regulation* / drug effects
  • Humans
  • Interleukin-6 / pharmacology
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Molecular Sequence Data
  • Open Reading Frames
  • Promoter Regions, Genetic*
  • Protein Isoforms / metabolism
  • Proteins / genetics*
  • RNA, Messenger / genetics
  • Recombinant Proteins / biosynthesis
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Transfection


  • CCAAT-Enhancer-Binding Proteins
  • GADD45 protein
  • Interleukin-6
  • Intracellular Signaling Peptides and Proteins
  • Protein Isoforms
  • Proteins
  • RNA, Messenger
  • Recombinant Proteins
  • Transcription Factors