NUCLEIC ACIDS, PROTEIN SYNTHESIS, AND MOLECULAR GENETICS
Retinoic Acid Stimulation of the Human Surfactant Protein B Promoter Is Thyroid Transcription Factor 1 Site-dependent*

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Surfactant B (SP-B) is a 79-amino acid peptide critical to postnatal respiratory adaptation. Expression of SP-B by respiratory epithelial cells is regulated by developmental and hormonal influences at the level of gene transcription. Previous studies supported the role of retinoic acids (RA) and their receptors (RARs) inSP-B gene transcription. In the present study, RARα was detected in mouse alveolar type II epithelial cells where SP-B is synthesized and processed. Deletion and site-specific mutagenesis analysis identified clustered retinoic acid-responsive element sites in the 5′-flanking enhancer region of the hSP-B gene that bound RARα proteins. RAR coactivators ACTR, SRC-1, and transcriptional intermediary factor 2 (TIF2) stimulated human (h) SP-B promoter activity in a dose-dependent fashion in pulmonary adenocarcinoma H441 cells. In addition, an RAR-associated protein, CREB-binding protein (CBP), potentiated the effects of RAR on hSP-B promoter activity in H441 cells. Importantly, RA stimulation of the hSP-B promoter depends on tissue-specific thyroid transcription factor (TTF-1) DNA-binding sites. TTF-1 protein synergistically stimulated the hSP-B promoter with RARα, CBP, and nuclear receptor coactivators in H441 cells. In addition, TTF-1 interacted directly with RARα and TIF2 in the mammalian two-hybrid system. These findings support a model in which RAR/retinoid X receptor, TTF-1, coactivators, and CBP form a transcription activation complex in the upstream enhancer region of thehSP-B gene.

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This work was supported by an American Lung Association grant (to C. Y.), NHLBI Grant HL-61803 from the National Institutes of Health (to C. Y.), and Specialized Center of Research Grants HL-56387 (to J. A. W. and C. Y.) and HL38859 (to J. A. W.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The first two authors contributed equally to this work.