A systems biology dynamical model of mammalian G1 cell cycle progression

The current dogma of G1 cell-cycle progression relies on growth factor-induced increase of cyclin D:Cdk4/6 complex activity to partially inactivate pRb by phosphorylation and to sequester p27Kip1-triggering activation of cyclin E:Cdk2 complexes that further inactivate pRb. pRb oscillates between an active, hypophosphorylated form associated with E2F transcription factors in early G1 phase and an inactive, hyperphosphorylated form in late G1, S and G2/M phases. However, under constant growth factor stimulation, cells show constitutively active cyclin D:Cdk4/6 throughout the cell cycle and thereby exclude cyclin D:Cdk4/6 inactivation of pRb. To address this paradox, we developed a mathematical model of G1 progression using physiological expression and activity profiles from synchronized cells exposed to constant growth factors and included a metabolically responsive, activating modifier of cyclin E:Cdk2. Our mathematical model accurately simulates G1 progression, recapitulates observations from targeted gene deletion studies and serves as a foundation for development of therapeutics targeting G1 cell-cycle progression.