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

Abstract

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/EBPδ gene expression during G0 growth arrest is a general property of mammary-derived cell lines. C/EBPδ is not induced during G0 growth arrest in 3T3 or IEC18 cells. C/EBPδ induction is G0-specific in mouse mammary epithelial cells; C/EBPδ gene expression is not induced by growth arrest in the G1, S, or G2 phase of the cell cycle. C/EBPδ antisense-expressing cells (AS1 cells) maintain elevated cyclin D1 and phosphorylated retinoblastoma protein levels and exhibit delayed G0 growth arrest and apoptosis in response to serum and growth factor withdrawal. Conversely, C/EBPδ-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 G0 growth arrest and apoptosis in response to serum and growth factor withdrawal. When C/EBPδ levels were rescued in AS1 cells by transfection with a C/EBPδ 'sense' construct, normal G0 growth arrest and apoptosis were restored. These results demonstrate that C/EBPδ plays a key role in the regulation of G0 growth arrest and apoptosis in mammary epithelial cells.