The Lung-Specific Surfactant Protein B Gene Promoter Is a Target for Thyroid Transcription Factor 1 and Hepatocyte Nuclear Factor 3, Indicating Common Factors for Organ-Specific Gene Expression along the Foregut Axis

• Published in: Molecular and cellular biology Vol. 14; no. 9; pp. 5671 - 5681
• Main Authors: Bohinski, Robert J., Di Lauro, Roberto, Whitsett, Jeffrey A.
• Format: Journal Article
• Language: English
• Published: Taylor & Francis 01.09.1994
• ISSN: 1098-5549; 1098-5549
• DOI: 10.1128/mcb.14.9.5671-5681.1994

We used the lung epithelial cell-specific surfactant protein B (SPB) gene promoter as a model with which to investigate mechanisms involved in transcriptional control of lung-specific genes. In a previous study, we showed that the SPB promoter specifically activated expression of a linked reporter gene in the continuous H441 lung cell line and that H441 nuclear proteins specifically protected a region of this promoter from bp -111 to -73. In this study, we further show that this region is a complex binding site for thyroid transcription factor 1 (TTF-1) and hepatocyte nuclear factor 3 (HNF-3). Whereas TTF-1 bound two highly degenerate and closely spaced sites, HNF-3 proteins bound a TGT3 motif (TGTTTGT) that is also found in several liver-specific gene regulatory regions, where it appears to be a weak affinity site for HNF-3. Point mutations of these binding sites eliminated factor binding and resulted in significant decreases in transfected SPB promoter activity. In addition, we developed a cotransfection assay and showed that a family of lung-specific gene promoters that included the SPB, SPC, SPA, and Clara cell secretory protein (CCSP) gene promoters were specifically activated by cotransfected TTF-1. We conclude that TTF-1 and HNF-3 are major activators of lung-specific genes and propose that these factors are involved in a general mechanism of lung-specific gene transcription. Importantly, these data also show that common factors are involved in organ-specific gene expression along the mammalian foregut axis.