Regulation of Gadd45γ expression by C/EBP

The Gadd45 gamma (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 Gadd45 gamma 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 Gadd45 gamma promoter. In addition, a noncanonical C/EBP-binding site within the Gadd45 gamma promoter where C/EBP beta and C/EBP delta could bind, was identified by electrophoretic mobility shift assay (EMSA) and reporter gene analysis. Furthermore, we found a coordinated expression profile between Gadd45 gamma mRNA and C/EBPs (beta and delta) protein during the differentiation of M1 cells: the amount of Gadd45 gamma transcripts became maximal when both C/EBP beta and C/EBP delta 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 Gadd45 gamma.