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Requirement for IGF-I in Epidermal Growth Factor-Mediated Cell Cycle Progression of Mammary Epithelial Cells

Department of Neuroscience & Anatomy, Penn State College of Medicine, Hershey, Pennsylvania 17033

Address all correspondence and requests for reprints to: Teresa L. Wood, Ph.D., Department of Neuroscience & Anatomy H109, Penn State College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033. E-mail: . twood{at}psu.edu

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 TGF 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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