Osteoprotegerin ligand induces β-casein gene expression through the transcription factor CCAAT/enhancer-binding protein β

Abstract

Osteoprotegerin ligand (OPGL, also known as RANKL), a member of the tumor necrosis factor superfamily, is essential for mammary gland development during pregnancy in addition to key roles in the immune system and bone development. Here we show that OPGL induces β-casein transcription through the CCAAT/enhancer-binding protein β (C/EBPβ). In both HC11 cell lines and primary mammary epithelial cells, OPGL stimulation triggers rapid nuclear translocation of C/EBPβ, which is critical for the expression of the β-casein gene. Mutation of C/EBPβ binding sites in the β-casein gene promoter completely abrogated OPGL-induced β-casein promoter activity. By contrast, OPGL stimulation did not result in STAT5 phosphorylation. In vivo immunohistochemistry studies further demonstrated defective nuclear translocation of C/EBPβ, but normal STAT5 activation, in OPGL-deficient mice. These data show that OPGL is a critical activator of β-casein gene expression via the transcription factor C/EBPβ. Our data provide new insights into the understanding of the molecular events involved in milk protein gene expression.