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Multiple mechanisms for oxygen‐induced regulation of the Clara cell secretory protein gene
Author(s) -
Ramsay Patricia L.,
Luo Ziqiang,
Major Angela,
Park Moon S.,
Finegold Milton,
Welty Steven E.,
Kwak Inseok,
Darlington Gretchen,
Demayo Francesco J.
Publication year - 2003
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/fj.03-0048fje
Subject(s) - hyperoxia , psychological repression , microbiology and biotechnology , enhancer , ccaat enhancer binding proteins , biology , transcription (linguistics) , transcription factor , activator (genetics) , gene isoform , gene expression , regulation of gene expression , messenger rna , promoter , gene , chemistry , dna binding protein , biochemistry , oxygen , linguistics , philosophy , organic chemistry
ABSTRACT The Clara cell secretory protein (CCSP) imparts a protective effect to the lung during oxidant injury. However, exposure to supplemental oxygen, a common therapeutic modality for lung disease, represses the expression of CCSP in the adult mouse lung. We investigated the mechanisms of hyperoxia‐induced repression of the mouse CCSP promoter. Deletion experiments in vivo and in vitro indicated that the hyperoxia‐responsive elements are localized to the proximal ‐166 bp of the CCSP promoter. Electrophoretic mobility shift and supershift analyses demonstrated increased binding of c‐Jun at the activator protein‐1 site, increased binding of CCAAT/enhancer binding protein (C/EBP) β at the C/EBP sites, and decreased binding at the Nkx2.1 sites. Western analyses revealed that hyperoxia exposure induced an increase in the expression of the C/EBPβ isoform liver‐inhibiting protein (LIP) and an increase in cytoplasmic Nkx2.1. Cotransfection of LIP or c‐Jun expression plasmids decreased the transcriptional activity of the proximal ‐166‐bp CCSP promoter. These observations suggest that hyperoxia‐induced repression of the CCSP gene is mediated, at least in part, at the level of transcription and that multiple mechanisms mediate this repression. Moreover, these novel observations may provide insights for generation of therapeutic interventions for the amelioration of oxidant‐induced lung injury.