Am. J. Respir. Cell Mol. Biol., Volume 24, Number 1, January, 2001 30-37

BR22, a Novel Protein, Interacts with Thyroid Transcription Factor-1 and Activates the Human Surfactant Protein B Promoter

Yih-Sheng Yang,^* Meng-Chun W. Yang,^* Bin Wang, and Jonathan C. Weissler

Department of Internal Medicine, Pulmonary and Critical Care Medicine, UT Southwestern Medical Center, Dallas, Texas

Surfactant protein (SP)-B expression is restricted to type II pneumocytes and Clara cells in the lung. Previously, a promoter region of human SP-B gene from 64 to 118 has been identified as critical for the tissue-specific expression of this gene. Two cis-elements for thyroid transcription factor (TTF)-1 and hepatocyte nuclear factor (HNF)-3 binding were found within this area. Using an oligonucleotide fragment, we incorporated this region sequence into the promoter of a HIS3 reporter gene in yeast. With this modified yeast a human lung complementary DNA (cDNA) library was screened for DNA-binding proteins, other than TTF-1 and HNF-3, that interacted with this promoter segment. A cDNA clone encoding a novel polypeptide, BR22, was identified that activated the reporter gene expression in yeast. This gene is expressed in many tissues and encodes a protein with bipartite nuclear localization signals. Studies using in vivo yeast two-hybrid analysis, in vitro protein-protein interactions, and coimmunoprecipitation analyses demonstrated that BR22 formed a protein complex with TTF-1. In vivo cotransfection studies further indicated that BR22 could act with TTF-1 to synergistically activate the SP-B promoter in mammalian cells. Our data suggest that BR22 is a TTF-1-associated protein. Through a protein-protein interaction with TTF-1, BR22 can form a complex and activate the human SP-B promoter in vivo.

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