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

Abstract

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)-3alpha 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-3alpha, 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.

The Paired Domain-containing Factor Pax8 and the Homeodomain-containing Factor TTF-1 Directly Interact and Synergistically Activate Transcription

“…TTF-1 interacts with retinoic acid receptors and co-factors (40), AP-1 family members (41), BR22 (42), CBP/p300 (43), TGD (T:G mismatch-specific thymine DNA glycosylase) (44), and GATA-6 (15). Pax8, as it has already been observed for other members of the pax gene family (30,45), could play a role in the recruitment to the Tg promoter of other factors, like TTF-1, and one or more co-activators.…”

Nkx2-1: a novel tumor biomarker of lung cancer

“…The centralized homeodomain is known to bind to other transcription factors, including retinoic acid receptors (RARs) (Yan et al, 2001), zinc finger GATA transcription-6 (GATA-6) (Liu et al, 2002;Weidenfeld et al, 2002), and nuclear factor of activated T cells (NFAT) (Dave et al, 2004). Finally, the COOH-terminus functionally interacts with the DNA repair protein thymine DNA glycosylase (TDG) (Missero et al, 2001), other transcriptional coactivators such as p300 (Bachurski et al, 2003;Grasberger et al, 2005), SRC-3, SRC-2, BR22 (amino acid 6-206) (Yang et al, 2001;2003), poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1), PARP-2 (Maeda et al, 2006), and other transcription factors such as nuclear factor κB (NF-κB) (Islam and Mendelson, 2006), signal transducers and activators of transcription 3 (STAT3) (Yan et al, 2002), Drosophila mothers against decapentaplegic 3 (SMAD3) (Li et al, 2002), nuclear factor I (NFI) (Missero et al, 2001), and ezrinradixin-moesin (ERM) (Lin et al, 2006).…”

GATA-6 and Thyroid Transcription Factor-1 Directly Interact and Regulate Surfactant Protein-C Gene Expression

“…TTF-1 binds and interacts with BR22, RARs, and CBP/P300 in complexes involved in the activation of the sp-B gene promoter (15,30,33). Likewise, TTF-1 binds and synergistically activates the sp-C promoter with nuclear factor-1, binding at sites located Ϫ307 to Ϫ91, in close proximity to both GATA-6 and TTF-1-binding sites.…”

“…There is increasing evidence that TTF-1 functions cooperatively with a number of other transcription factors, forming complexes on regulatory regions of target genes. TTF-1 interacts with retinoic acid receptors (RARs) and associated cofactors (13), nuclear factor-1, 2 AP1 family members (14), and BR22 (15). Depending on the sites and context of elements within target genes, TTF-1 can act directly or cooperatively with these various factors to regulate gene expression.…”