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Transcriptional Regulation of Ceruloplasmin by FOXO1A and IL‐6
Author(s) -
Hollenbach Andrew Durrell,
Miller Patrick J.,
Sidhu Alpa
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.lb199
Subject(s) - ceruloplasmin , transcription factor , inflammation , transcriptional regulation , promoter , transcription (linguistics) , cancer research , chemistry , gene , biology , gene expression , microbiology and biotechnology , immunology , biochemistry , linguistics , philosophy
Ceruloplasmin (Cp), a six‐copper containing protein synthesized and secreted mainly by the liver, is an important extracellular anti‐oxidant and is part of the acute phase reaction during inflammation. The increase in hepatic expression and serum concentration of Cp during inflammation, infection, and trauma is primarily mediated by the inflammatory cytokine IL‐6. IL‐6 is known to positively regulate the transcription of Cp through its proximal promoter region. In addition, IL‐6 treatment localizes FOXO1A, a winged‐helix transcription factor, to the nucleus leading to its participation in IL‐6 induced gene expression. Microarray analysis showed that the expression of Cp increased 16 fold in the presence of a constitutively active FOXO1A. Consistent with this data we demonstrate for the first time that Cp is a direct transcriptional target of FOXO1A in an IL‐6 dependent manner. Through in vitro and in vivo mutational analysis, we identify the exact DNA recognition site for FOXO1A in the Cp proximal promoter region. We also demonstrate for the first time that both IL‐6 and FOXO1A are required for the transcriptional activity of Cp in HepG2 cells, identifying an additional role of FOXO1A in the inflammatory process. Funding: National Institutes of Health Centers of Biomedical Research Excellence (1 P20 RR020152 ) and the Louisiana Cancer Research Consortium Competitive Advantage Fund