The regulation of CCAAT/enhancer-binding protein-delta expression by activated Stat3

The CCAAT/Enhancer Binding Protein family of transcription factors is implicated in the regulation of cell proliferation and differentiation in a variety of tissues. C/EBPδ is involved in regulating cell cycle exit and apoptosis of mammary epithelial cells after serum and growth factor withdrawal. In vivo, C/EBPδ is upregulated in the involuting mouse mammary gland, a time of massive mammary epithelial apoptosis. In mouse mammary epithelial cells, C/EBPδ is regulated by increased transcription.; The increased transcription of C/EBPδ during cell cycle exit after serum and growth factor withdrawal is due to the activity of a C/EBPδ promoter fragment located between −81 and −127 by upstream of the transcription start site. Stat3 activation, with binding of phospho-Stat3 to the Acute Phase Response Element (APRE) in this region of the C/EBPδ promoter, is responsible for the induction of C/EBPδ during G₀ growth arrest of mammary epithelial cells. This increase in Stat3 activation and C/EBPδ transcription after serum and growth factor withdrawal is unique to mammary epithelial cells.; Oncostatin M, an Interleukin 6 type cytokine, also induces sustained Stat3 activation and upregulation of C/EBPδ with subsequent G₀ growth arrest in mouse and human mammary epithelial cells. Furthermore, the growth inhibition induced by Oncostatin M depends upon the presence of C/EBPδ.; The pathways leading to activation of Stat3 with increased transcription of C/EBPδ and subsequent G₀ growth arrest of mammary epithelial cells are different for serum and growth factor withdrawal and treatment with Oncostatin M. Serum and growth factor deprivation activates Stat3 by a calcium dependent mechanism, without activation of members of the Janus kinase family of non-receptor tyrosine kinases. In contrast, Oncostatin M activates Stat3 by a Janus kinase dependent, calcium independent mechanism. Inhibition of the Stat3-C/EBPδ pathway by chelation of intracellular calcium inhibits the ability of mammary epithelial cells to exit the cell cycle after serum and growth factor deprivation, thus providing further evidence of the importance of C/EBPδ in mammary epithelial cell cycle exit. Taken together, these data suggest an important role for the Stat3-C/EBPδ pathway in growth arrest of mammary epithelial cells.