title: Autoregulation enables different pathways to control CCAAT/enhancer binding protein beta (C/EBP beta) transcription.
abstract: CCAAT/enhancer binding protein beta (C/EBP beta) also named liver-enriched transcriptional activating protein (LAP) is a member of the C/EBP family of transcription factors and is involved in hepatocyte-specific gene expression and in the process of tissue differentiation. The activity of LAP/C/EBP beta can be regulated at the transcriptional and posttranslational level or by protein-protein interaction with other transcription factors. In this study we show that LAP/C/EBP beta can stimulate its own transcription. Deletion analysis of the rat LAP/C/EBP beta promoter in luciferase reporter gene experiments demonstrated that the region located between nucleotide -121 to -71, comprising two recently characterized cAMP responsive element (CRE)-like elements, is important for autoregulation. Gel shift experiments using oligonucleotides with overlapping point mutations identified the sequence GCAATGA (beta-site) adjacent to and partially overlapping the first CRE-like site as core motif for LAP/C/EBP beta binding. Analysis of a mutated beta-site in reporter gene experiments showed the functional relevance of this site for autoregulation. The composite C/EBP beta-CRE-element in the promoter enables synergistic activation of transcription by LAP/C/EBP beta and the protein kinase A (PKA)/cAMP responsive element binding protein (CREB) pathway in a cell-type specific manner. In hepatoma cells nuclear factor kappa B (NF-kappa B) increased autoregulation and therefore could mediate enhanced activation during inflammatory responses. In summary, our results demonstrated that the assembly of the three binding sites in the promoter and thus the interaction between LAP/C/EBP beta and members of the CREB or NF-kappa B family allows the control of LAP/C/EBP beta gene transcription as a response to different stimuli in a tissue specific manner.
authors.affiliation: Department of Gastroenterology and Hepatology, Medizinische Hochschule, Cal-Neuberg-Str. 1, D30625 Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Niehof
authors.forename: S
authors.initials: S
authors.lastname: Kubicka
authors.forename: L
authors.initials: L
authors.lastname: Zender
authors.forename: M P
authors.initials: MP
authors.lastname: Manns
authors.forename: C
authors.initials: C
authors.lastname: Trautwein
mesh_terms: D000818:Animals; D001665:Binding Sites; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018983:DNA Footprinting; D003850:Deoxyribonuclease I / Q000378:metabolism; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009928:Organ Specificity; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D020218:Response Elements / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D017362:Cyclic AMP Response Element-Binding Protein; D016328:NF-kappa B; D003850:Deoxyribonuclease I