CCAAT/enhancer-binding protein δ regulates mammary epithelial cell G0 growth arrest and apoptosis

CCAAT/enhancer-binding proteins (C/EBPs) are a highly conserved family of DNA-binding proteins that regulate cell-specific growth, differentiation, and apoptosis. Here, we show that induction of C/EBP delta gene expression during G(0) growth arrest is a general property of mammary-derived cell lines. C/EBP delta is not induced during G(0) growth arrest in 3T3 or IEC18 cells. C/EBP delta induction is G(0)-specific in mouse mammary epithelial cells; C/EBP delta gene expression is not induced by growth arrest in the G(1), S, or G(2) phase of the cell cycle. C/EBP delta antisense-expressing cells (AS1 cells) maintain elevated cyclin D1 and phosphorylated retinoblastoma protein levels and exhibit delayed G(0) growth arrest and apoptosis in response to serum and growth factor withdrawal. Conversely, C/EBP delta-overexpressing cells exhibited a rapid decline in cyclin D1 and phosphorylated retinoblastoma protein levels, a rapid increase in the cyclin-dependent kinase inhibitor p27, and accelerated G(0) growth arrest and apoptosis in response to serum and growth factor withdrawal. When C/EBP delta levels were rescued in AS1 cells by transfection with a C/EBP delta "sense" construct, normal G(0) growth arrest and apoptosis were restored. These results demonstrate that C/EBP delta plays a key role in the regulation of G(0) growth arrest and apoptosis in mammary epithelial cells.