Comparative sequence analysis of the mouse and human transferrin promoters: Hormonal regulation of the transferrin promoter in Sertoli cells

Cell-specific expression of the iron-binding protein transferrin is in part mediated through the regulation of its promoter. Although all cells require iron from serum transferrin produced by hepatocytes, cells that create a blood barrier such as Sertoli cells in the testis and choroid plexus epithelium in the brain also express the transferrin gene to provide iron to cells sequestered within the serum-free environment. The current study provides a complete sequence of the 3-kb mouse transferrin promoter and makes a comparison with the sequence available for the human transferrin promoter. Conserved regulatory elements between these two species are identified and speculated to be potentially important response elements for the regulation of the transferrin gene. The proximal 90 bp of the mouse and human transferrin promoter was found to be 80% homologous. The previously identified protected regions in the proximal human promoter also were conserved in the mouse transferrin promoter. Our sequence analysis data revealed that an E-box response element is also conserved between mouse and human promoters. Deletion mutants of the mouse transferrin promoter were generated in CAT reporter constructs to study the regulation of the transferrin promoter in Sertoli cells. As in the case of the human transferrin promoter, the mouse 581-bp proximal transferrin promoter was sufficient to obtain basal expression. A putative cyclic AMP response element (CRE) in the minimal promoter may be needed for follicle-stimulating hormone (FSH) actions mediated via cyclic AMP. Interestingly, other regulatory agents such as the testicular paracrine factor PModS used elements in the upstream region. A repressor was identified 2.5 kb upstream from the start site of translation. Combined observations suggest for the first time that a minimal promoter is sufficient for basal transcription, but the upstream regions of the promoter are needed for the hormonal regulation of the transferrin gene in Sertoli cells. Conserved response elements between the mouse and human sequences identify potentially important regulatory elements of the promoter and are discussed. (C) 1998 Wiley-Liss, Inc.