Regulation of Gadd45gamma expression by C/EBP.
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.
Jung
N
N
Therapeutic Gene Group, Team 1, Samyang Genex Biotech Res. Inst., Yusung-Gu, Taejeon, Korea.
Yi
Y W
YW
Kim
D
D
Shong
M
M
Hong
S S
SS
Lee
H S
HS
Bae
I
I
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D003001:Cloning, Molecular; D004249:DNA Damage; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000378:metabolism; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D000097642:GADD45 Proteins
D022762:CCAAT-Enhancer-Binding Proteins; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D020033:Protein Isoforms; D011506:Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014157:Transcription Factors; D000097642:GADD45 Proteins