Signal transducer and activator of transcription 3 activates CCAAT enhancer-binding protein delta gene transcription in G(0) growth-arrested mouse mammary epithelial cells and in involuting mouse mammary gland

The CCAAT enhancer-binding protein (C/EBP) family of transcription factors is implicated in the regulation of cell proliferation and differentiation i n a variety of tissues. C/EBP delta is involved in regulating G(0) growth a rrest and apoptosis of mouse mammary epithelial cells. This study shows tha t activation of signal transducer and activator of transcription 3 (Stat3), but not activation of Stat1 or Stat5, occurs concurrently with G(0) growth arrest of HC11 mouse mammary epithelial cells, but not NIH 3T3 fibroblasts . Promoter analysis demonstrates that the C/EBP delta promoter fragment inv olved in transcriptional activation during G(0) growth arrest contains a St at3 binding site and that mutation of this site eliminates the G(0) growth arrest inducibility of the C/EBP delta promoter. Overexpression of Stat3 in creases C/EBP delta promoter activity during G(0) growth arrest of HC11 cel ls, whereas dominant negative Stat3 decreases C/EBP delta promoter activity under the same conditions. Neither Stat3 overexpression nor dominant negat ive Stat3 expression influences C/EBP delta promoter activity in growing HC 11 cells or G(0) growth-arrested NIH3T3 cells, demonstrating that the effec t is specific to G(0) growth arrest of mammary epithelial cells. Band shift assays and antibody interference assays demonstrate specific binding of St at3 to the acute phase response element in the C/EBP delta promoter in G(0) growth-arrested HC11 cell extracts and 24 h involuting mouse mammary gland extracts. These data indicate that Stat3 activates C/EBP delta transcripti on in G(0) growth-arrested mouse mammary epithelial cells and binds to the C/EBP delta promoter during involution, An autocrine mechanism of Stat3 act ivation is proposed.