Cell type-specific expression of the human transferrin gene. Role of promoter, negative, and enhancer elements.

Transferrin (Tf), the iron transport protein of vertebrate serum, is mainly synthesized in the liver. cis-Acting DNA elements required for liver-specific expression of the human Tf gene were identified by transient and stable expression assays in human hepatoma (HepG2 and Hep3B) and epithelial carcinoma (HeLa) cell lines. Deletion analysis of the 5' DNA sequences of the gene have defined four functionally different regions: (a) A cell type-specific promoter located between positions -125 and -45 which interacts with two nuclear factors and is sufficient for liver-specific expression. (b) A distal promoter region from -620 to -125 base pairs containing positive and negative cis-acting elements which regulate the promoter activity. (c) A negative-acting region between -1.0 and -0.6 kilobase pairs which down-regulates transcription from the Tf promoter. (d) An enhancer located between -4.0 and -3.3 kilobase pairs which is more active in hepatoma than in HeLa cells. Thus, Tf gene expression is modulated by a combination of multiple positive and negative cis-acting elements. The expression results are discussed with respect to our previous description of the trans-acting factors interacting with the proximal and distal promoter regions.