Surfactant protein-A (SP-A) gene expression is developmentally regulated in fetal lung type II cells in concert with surfactant glycerophospholipid synthesis. In studies using transfected type II cells, we characterized a nuclear receptor element (NRESP-A, 5′-TGACCTTA-3′) at -242 bp in the 5′-flanking sequence of human SP-A2 (hSP-A) gene that is essential for basal and cAMP-induced expression. NRESP-A has high sequence similarity to the consensus binding site for estrogen-related receptor (ERR). In the present study, we observed that ERRα and ERRγ, but not ERRβ, were expressed in human fetal lung type II cells. In vitro transcribed/translated ERRα and ERRγ bound to the NRE SP-A; DNase I footprinting using bacterially expressed ERRα revealed a single DNase I protected region that included NRESP-A. In transient transfection assays of COS-7 and primary cultures of lung type II cells, ERRα acting through NRESP-A increased hSP-A promoter activity, whereas ERRγ had no effect. ERRα overexpression in lung type II cells enhanced cAMP induction of endogenous hSP-A expression, whereas cotransfection of protein kinase A catalytic subunit enhanced ERRα stimulation of hSP-A promoter activity in lung adenocarcinoma cells. Mice homozygous null for the ERRα gene manifested decreased SP-A expression relative to wild-type and heterozygous littermates. The ERRα-specific inverse agonist XCT790 inhibited cAMP induced hSP-A expression in human fetal lung type II cells in a concentration-dependent manner, suggesting a role of peroxisome proliferator-activated receptor-γ coactivator 1α. These findings suggest that ERRα acting through NRESP-A is an important mediator of hSP-A gene expression and its induction by cAMP.
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