Hormonal regulation of transcription factor activity in mammary epithelial cells

Abstract

The multihormonal control of milk protein gene transcription in mammary epithelial cells has been investigated. Although the hormones regulating milk protein gene expression are known, the interaction of the signal transduction pathways of steroid (glucocorticoids) and peptide (insulin and prolactin) hormones remains undefined in molecular terms. These signals converge on the level of nuclear factors binding to regulatory elements in the β-casein gene promoter. The promoter has a modular architecture and is composed of positive and negative response elements. Nuclear transcription factors which bind to these elements have been identified. The mammary gland factor, MGF, is an essential mediator of lactogenic hormone action and is itself positively regulated in its DNA binding activity. It binds to the promoter region between positions −80 to −100. MGF counteracts a repressor element, constituted by two components, which is located adjacent to the MGF binding site at positions −100 to −150. The transcription factor YY1 binds to the proximal half of the repressor element which overlaps with the MGF binding site. Specific single-stranded DNA binding proteins contribute to the negative regulation of the promoter by interacting with sequence elements between −160 and −190. DNA binding of these proteins is negatively regulated by the lactogenic hormones.