The C/EBPβ transcription factor regulates epithelial cell proliferation and differentiation in the mammary gland

Abstract

Studies of C/EBP␤-deficient mice have demonstrated a pivotal role for this transcription factor in hematopoiesis, adipogenesis, and ovarian function. Here we show that C/EBP␤ is also essential for normal development and function of the mammary gland. Ductal morphogenesis in virgin C/EBP␤-deficient mice was disrupted, with ducts displaying reduced growth and branching. To distinguish whether the effect of C/EBP␤ deficiency on mammary epithelium is indirect or cell autonomous, we performed ovarian and mammary gland transplants. Transplants of wild-type ovaries into mutant females partially restored ductal morphogenesis during puberty but failed to support mammopoiesis during pregnancy. At term, mutant mice harboring wild-type ovaries exhibited reduced alveolar proliferation and impaired epithelial cell differentiation, including a complete absence of milk protein expression. Mammary gland transplant experiments demonstrated that development of C/EBP␤-deficient epithelium was defective within a wild-type stroma and host background. Cell proliferation during pregnancy was reduced and differentiation, as measured by the activity of milk protein genes, was inhibited. However, wild-type epithelium developed in a C/EBP␤-deficient stroma. Thus, C/EBP␤ plays an essential, cell autonomous role in the proliferation and differentiation of mammary secretory epithelial cells and is required for the activation of milk protein genes.

C/EBPβ Participates in Regulating Transcription of the p53 Gene in Response to Mitogen Stimulation

“…It has also been shown to transactivate the c-fos serum response element upon activation of the Ras-dependent signaling pathway in response to mitogenic stimulation (31). C/EBP␤ is found to be constitutively expressed in the liver, intestine, lung, adipose tissue, spleen, and kidney (39 -43) and plays an important role in adipocyte (40,44), hepatocyte (45), and mammary gland differentiation (29), as well as in ovulation (32,46). C/EBP␤ knock-out mice (43) have alteration in glucose homeostasis (47), immunological defects (48), develop lymphoproliferative disorders (49,50) and defects in female reproduction and infertility (32).…”

“…A data base search to identify candidate transcription factors that may bind the p53 promoter within the Ϫ972/Ϫ953 region as well as some preliminary DNA-binding assays revealed one factor (C/EBP␤) as a likely candidate. C/EBP␤ is a CCAAT enhancer-binding protein and is critical for normal proliferation and differentiation of mammary epithelial cells (29,30,34,38) as well as numerous other cell types (27,28). It has also been shown to transactivate the c-fos serum response element upon activation of the Ras-dependent signaling pathway in response to mitogenic stimulation (31).…”

“…Here we have demonstrated that the transcription factor C/EBP␤ (CAAT/enhancer-binding protein-␤) binds to this regulatory site on the p53 promoter in response to mitogen stimulation and serves to increase p53 promoter expression as cells enter S phase. Because C/EBP␤ is a transcription factor that is critical for normal proliferation and differentiation of a number of cell types (27)(28)(29)(30) and has also been demonstrated to play a role in mitogen-stimulated induction of cell division (31), we have carried out a experiments to establish whether it also has a role in regulating p53.…”

Conditional ablation of C/EBPβ demonstrates its keratinocyte-specific requirement for cell survival and mouse skin tumorigenesis

“…As shown in Figure 2a, C/EBPb protein was not detected in the epidermis of K5-Cre;C/EBPb fl/fl mice (faster mobility band in epidermis is non specific) but was present at normal levels in the other organs examined. Furthermore, K5-Cre; C/EBPb fl/fl females were fertile and lactation competent, indicating that ovarian and mammary gland defects present in C/EBPb À/À mice (Sterneck et al, 1997;Robinson et al, 1998) did not occur in the K5-Cre; C/EBPb fl/fl mice. In addition, K5-Cre; C/EBPb fl/fl mice exhibited normal immunostaining for C/EBPb in pulmonary alveolar macrophages of lung sections histological sections (data not shown) and no cases of splenomegaly (0/19), which is due to elevated IL-6 levels in C/EBPb null mice (Screpanti et al, 1996) were observed in K5-Cre;C/EBPb fl/fl mice.…”

C/EBPβ, but not C/EBPα, is essential for ductal morphogenesis, lobuloalveolar proliferation, and functional differentiation in the mouse mammary gland

“…Because C/EBP␣ expression does not appear to be restricted to pregnancy and lactation, these results do not support a cascade model of C/EBP regulation during mammary gland development. Instead, both C/EBP␤ and C/EBP␣ mRNAs are expressed coordinately during mid-to-late pregnancy and lactation (see Robinson et al 1998). (B, lanes 4,5,8,9; C, lanes 1,2,5,6).…”