Mitogenic signaling in MCF-7 cells. The resumption of cell cycle progression in quiescent MCF-7 cells requires cooperation between two signaling pathways: ER-dependent transcription and PI3K/Akt activity. In the absence of ligand, the ER-dependent transcription proceeds at baseline level. This is sufficient to complement the growth factor-stimulated kinase cascades (Ras/MAPK and PI3K/Akt) to achieve sufficient level of expression of early- and late-G1 genes. The cell concentration of the encoded proteins such as cyclin D1 is also regulated by post-transcriptional processes (e.g. translational regulation by mTOR). The G1/S transition requires in addition the cascade of cyclin-dependent kinases whose activation requires the expression of the appropriate cyclins (D1, E, A) as well as specific phosphorylation and dephosphorylation of the kinases themselves. In the absence of growth factor stimulation, the basal activity of PI3K/Akt is sufficient to complement the full (estrogen-stimulated) transcriptional activation of ER to induce G1-phase progression.