The functional effects and mechanisms by which fibroblast growth factor 2 (FGF2) controls bovine mammary epithelial cells: Implications for the development and functionality of the bovine mammary gland1

Abstract

Fibroblast growth factor (FGF) signaling plays essential roles in tissue development and homeostasis. Accumulating evidence reveals that fibroblast growth factor 2 (FGF2) regulates ductal elongation, which requires cell proliferation and epithelial expansion in the mammary gland. However, the function and mechanisms by which FGF2 controls functionality of epithelial cells is less well defined. Here, we demonstrate the functional effects of FGF2 on bovine mammary epithelial (MAC-T) cells and the intracellular signaling mechanisms for these FGF2-induced actions. The current results show that treatment of MAC-T cells with a recombinant FGF2 induced cell proliferation and cell-cycle progression with increased expression of proliferating cell nuclear antigen and cyclin D1. Moreover, FGF2 increased phosphorylation of serine/threonine protein kinase (protein kinase B [AKT]), extracellular signal-regulated kinases 1 and 2 (ERK1/2), Jun N-terminal kinase (JNK), 70 kDa ribosomal S6 kinase (P70S6K), 90 kDa ribosomal S6 kinase (P90S6K), ribosomal protein S6 (S6), and cyclin D1 proteins. These FGF2-induced activations of signaling pathway proteins were inhibited by blocking AKT, ERK1/2, or JNK phosphorylation. The effect of FGF2 to stimulate MAC-T cell proliferation was mediated by activation of FGF receptors (FGFR) and AKT, ERK1/2, and JNK mitogen-activated protein kinase pathways in response to FGF2 stimulation. Furthermore, expression and activation of endoplasmic reticulum (ER) stress-related factors and ER stress-induced MAC-T cell death was reduced by FGF2. Together, these results suggest that the FGF2-FGFR-intracellular signaling cascades may contribute to maintaining and/or increasing numbers of mammary epithelial cells by inducing proliferation of mammary epithelial cells and by protecting cells from ER stress responses. Therefore, this study provides evidence that FGF2 signaling is a positive factor for mammary gland remodeling and for increasing persistency of milk production.

UFM1-Specific Ligase 1 Ligating Enzyme 1 Mediates Milk Protein and Fat Synthesis-Related Gene Expression via the JNK Signaling Pathway in Mouse Mammary Epithelial Cells

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Regulation of Hair Follicle Growth and Development by Different Alternative Spliceosomes of FGF5 in Rabbits

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Adipocyte-Derived Paracrine Factors Regulate the In Vitro Development of Bovine Mammary Epithelial Cells

“…In addition, several members of the FGF family are important stroma-derived mitogens involved in ruminant mammary gland development [59]. Jeong et al [61] used an in vitro model of MAC-T bovine mammary epithelial cells to study the signaling pathways induced by FGF-2. The authors showed that FGF-2 stimulated bMEC proliferation by activation of signaling pathways mediated by protein kinase B (PKB), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and Jun N-terminal kinase (JNK), and suggested that this growth factor may be important for increasing persistency of milk production [61].…”