Induction of GADD153, a CCAAT/enhancer-binding protein (C/EBP)-related gene, during the acute phase response in rats. Evidence for the involvement of C/EBPs in regulating its expression

• Published in: The Journal of biological chemistry Vol. 269; no. 31; pp. 20119 - 20125
• Main Authors: Sylvester, S L, ap Rhys, C M, Luethy-Martindale, J D, Holbrook, N J
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Biochemistry and Molecular Biology 05.08.1994
• Subjects: Acute-Phase Reaction - genetics; Animals; Base Sequence; Biological and medical sciences; CCAAT-Enhancer-Binding Proteins; DNA-Binding Proteins - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Humans; Inflammation; Lipopolysaccharides - pharmacology; Liver - metabolism; Lung - metabolism; Male; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; Nuclear Proteins - metabolism; Oligodeoxyribonucleotides; Promoter Regions, Genetic; Protein Biosynthesis; Proteins - genetics; Rats; Rats, Inbred F344; RNA, Messenger - biosynthesis; Transcription Factor CHOP; Transcription Factors; Transcription. Transcription factor. Splicing. Rna processing; Transcriptional Activation; Tumor Cells, Cultured; Vertebrata; Acute phase protein; Regulation(control); Mammalia; Transcription; Rat; Rodentia; Footprinting technique; Inflammation; Gel retardation technique; Transcription factor; Transcription factor C/EBP
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/s0021-9258(17)32135-x

CCAAT/enhancer-binding proteins (C/EBPs) comprise a homologous group of transcriptional regulators that control liver and fat differentiation and are involved in regulating the expression of acute phase reactants during the host response to inflammation. GADD153, a unique member of the C/EBP family, has been proposed to act as a dominant negative inhibitor of other C/EBPs, but little is known about its expression in liver or its role in the processes described above. We have examined its expression during the acute phase response (APR) and have shown that like C/EBP beta and C/EBP delta, GADD153 mRNA is markedly induced in livers of rats treated with lipopolysaccharide to initiate the APR. Interestingly, its induction is temporally delayed relative to that of C/EBP beta and C/EBP delta but is similar to that of acute phase reactants shown to be regulated by C/EBPs. Footprint analysis of the GADD153 promoter showed binding of proteins in liver extracts of both untreated and lipopolysaccharide-injected rats to a putative C/EBP regulatory site. Gel shift analysis showed that although present constitutively, binding activity was increased in extracts from lipopolysaccharide-treated animals. Both C/EBP alpha and C/EBP beta were shown to contribute to the binding activity with the contribution by C/EBP beta increasing during the APR. Support for the functional role of this C/EBP-binding site and its interaction with C/EBPs in regulating GADD153 expression was obtained with cultured HepG2 hepatoma cells in which overexpression of C/EBP beta was found to transactivate expression of a plasmid containing the GADD153 promoter linked to a reporter gene. These findings suggest that the GADD153 gene is itself regulated by C/EBPs during the host response to inflammation and that GADD153 is likely to contribute to the regulation of other genes whose expression is altered during the APR.