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Abstract
It has been reported that respiratory epithelium-specific transcription is mediated by thyroid transcription factor 1 and members of the HNF3/forkhead family of transcription factors. Here, we show that the uteroglobin/Clara cell 10-kDa promoters from rabbit and man are regulated by HNF3alpha and HNF3beta but not by HFH-4 and TTF-1. We have identified two HNF3-responsive elements in the rabbit uteroglobin/CC10 promoter located around 95 and 130 base pairs upstream of the transcriptional start site. Both elements contribute to promoter activity in H441 cells expressing uteroglobin/CC10 and HNF3alpha. Gene transfer experiments into Drosophila Schneider cells that lack many mammalian transcription factor homologs revealed that HNF3alpha and HNF3beta on their own cannot activate the uteroglobin/CC10 promoter. However, HNF3alpha and HNF3beta strongly enhanced Sp1-mediated promoter activation. Synergistic activation by HNF3alpha and Sp1 was absolutely dependent on the integrity of two Sp1 sites located at around -65 and -230. We show further that multiple activation domains of Sp1 are required for cooperativity with HNF3alpha. These studies demonstrate that transcription from the rabbit uteroglobin/CC10 promoter in lung epithelium is controlled by the combinatorial action of the cell-specific factor HNF3alpha and the ubiquitous factor Sp1.
Highlights
The level and pattern of expression of a gene is determined mainly by the combinatorial action of transcription factors binding to distinct promoter and enhancer elements
Studies of other genes expressed in lung epithelium provided evidence that thyroid transcription factor-1 (TTF-1), which is expressed in addition to the thyroid and the brain in lung type II and Clara cells [11, 12], is a major player involved in the expression of genes in the respiratory epithelium [13,14,15,16,17]
We demonstrate that the rabbit uteroglobin/CC10 gene promoter responds to the transcription factors hepatocyte nuclear factor 3 (HNF3)␣ and HNF3, but not to TTF-1 and HNF3/forkhead homologs (HFH)-4
Summary
The level and pattern of expression of a gene is determined mainly by the combinatorial action of transcription factors binding to distinct promoter and enhancer elements. We show that H441 cells express human uteroglobin/CC10 mRNA in addition to several other lung epithelial cell-specific mRNAs. We demonstrate that the rabbit uteroglobin/CC10 gene promoter responds to the transcription factors HNF3␣ and HNF3, but not to TTF-1 and HFH-4.
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