Abstract
Induction of cyclin proteins is required for progression of cells through the G1-S and G2-M cell cycle checkpoints and is a primary mechanism by which mitogens regulate cell cycle progression. IGF-I and the epidermal growth factor (EGF)-related ligands are mitogens for mammary epithelial cells in vitro and are essential for growth of the mammary epithelium during development. We report here that IGF-I in combination with EGF or TGFα is synergistic in promoting DNA synthesis in mammary epithelial cells in the intact mammary gland cultured in vitro. We further investigated the role of IGF-I and EGF in cyclin expression and cell cycle progression in the mammary gland and demonstrate that IGF-I and EGF induce expression of early G1 cyclins. However, we show that IGF-I, but not EGF, induces late G1 and G2 cyclins and is required for mammary epithelial cells to overcome the G1-S checkpoint. These data demonstrate that IGF-I is essential for cell cycle progression in mammary epithelial cells and that it is required for EGF-mediated progression past the G1-S checkpoint in these cells.
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