Abstract
BackgroundSecretoglobin (SCGB) 3A1 is a secretory protein of small molecular weight with tumor suppressor function. It is highly expressed in lung and trachea in both human and mouse, with additional tissues expressing the protein that differ depending on the species. However, little is known about the function and transcriptional regulation of this gene in normal mouse tissues.ResultsBy reporter gene transfection and gel mobility shift analyses, we demonstrated that expression of the mouse Scgb3a1 gene is regulated by a PU-box binding protein and a ubiquitous transcription factor NF-Y that respectively binds to the PU-boxes located at -99 to -105 bp and -158 to -164 bp, and the "CCAAT" binding sites located at -425 to -429 bp and -498 to -502 bp from the transcription start site of the gene. However, the effect of PU-box binding protein on transcriptional activation is minimal as compared to NF-Y, suggesting that NF-Y is a more critical transcription factor for mouse Scgb3a1 gene transcription. Despite that NF-Y is a ubiquitous factor, Scgb3a1 is highly expressed only in mouse lung and mtCC cells that are derived from SV40 transformed mouse Clara cells, but not in ten other mouse tissues/cells examined. Gene methylation analysis revealed that within 600 bp of the Scgb3a1 gene promoter region, there are nine CpG methylation sites present, of which two CpGs closest to the transcription start site of the gene are unmethylated in the tissues/cells expressing SCGB3A1.ConclusionA ubiquitous transcription factor NF-Y binds to and activates expression of the mouse Scgb3a1 gene and tissue-specific expression of the gene is associated with CpG methylation of the promoter.
Highlights
Secretoglobin (SCGB) 3A1 is a secretory protein of small molecular weight with tumor suppressor function
We demonstrate that a ubiquitous transcription factor NF-Y is an important transcription factor for controlling expression of the mouse Scgb3a1 gene through its binding to the responsive "CCAAT" element located at -425 to -429, and -498 to -502 bp upstream of the Scgb3a1 gene
Six mouse Scgb3a1 gene promoter-luciferase reporter constructs were prepared and subjected to transient transfection analysis using transformed mouse Clara cells that are derived from tumor tissues of lungs obtained from transgenic mice expressing the simian virus 40 large T antigen gene under control of uteroglobin/ Clara cell secretory protein promoter [13]
Summary
Secretoglobin (SCGB) 3A1 is a secretory protein of small molecular weight with tumor suppressor function. It is highly expressed in lung and trachea in both human and mouse, with additional tissues expressing the protein that differ depending on the species. The AKT signaling pathway is responsible for the SCGB3A1's tumor suppressor function as characterized by inhibition of cell growth, cell migration and invasion [9]. In this connection, it was shown that EGF and TGFγ increase SCGB3A1 expression through activation of the ERK-MAPK and phosphoinositide-3 kinase-AKT pathways [10]. The expression of SCGB3A1 is restricted to terminally differentiated airway epithelial cells and is upregulated during retinoic acid induced differentiation of bronchial epithelial cells, suggesting that SCGB3A1 may be involved in the acquisition or maintenance of the terminally differentiated epithelial phenotype [5]
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