Activation of CAAT enhancer-binding protein delta (C/EBPdelta) by interleukin-1 negatively influences apolipoprotein C-III expression.
Tissue-specific transcription of the apolipoprotein C-III (apoC-III) gene is mainly regulated by synergistic interactions between the liver-enriched transcription factor HNF-4, which binds to the proximal promoter, and ubiquitous factors, which bind to the upstream enhancer region. Here we show that apoC-III expression in HepG2 cells is negatively regulated in response to interleukin-1 (IL-1), and this inhibition is mainly due to transcriptional repression. CAAT enhancer-binding protein delta (C/EBPdelta) was found to be the main mediator of IL-1-induced suppression. Analysis of the apoC-III promoter revealed two IL-1 response elements. The first is located in the proximal promoter region D and the second in the distal enhancer region I. Proximal element D is a high affinity binding site for C/EBPdelta, while the enhancer element I is not directly recognized by this transcription factor. Functional analysis of different combinations of homologous and heterologous promoter constructs revealed that indirect interaction of C/EBPdelta with site I, in the context of the full promoter, leads to repression. C/EBPdelta is activated by phosphorylation during IL-1-induced signal transduction pathway. This modification is important for both DNA binding activity and indirect transrepression of the apoC-III promoter.
Lacorte
J M
JM
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas, P. O. Box 1527, Herakleion 711 10, Crete, Greece.
Ktistaki
E
E
Beigneux
A
A
Zannis
V I
VI
Chambaz
J
J
Talianidis
I
I
D000818:Animals; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D051743:CCAAT-Enhancer-Binding Protein-delta; D022762:CCAAT-Enhancer-Binding Proteins; D019556:COS Cells; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism
D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D022762:CCAAT-Enhancer-Binding Proteins; C497252:CEBPD protein, human; D004268:DNA-Binding Proteins; D007375:Interleukin-1; D016328:NF-kappa B; D009687:Nuclear Proteins; D014157:Transcription Factors; D051743:CCAAT-Enhancer-Binding Protein-delta