Abstract
Cells switch between quiescence and proliferation states for maintaining tissue homeostasis and regeneration. At the restriction point (R-point), cells become irreversibly committed to the completion of the cell cycle independent of mitogen. The mechanism involving hyper-phosphorylation of retinoblastoma (Rb) and activation of transcription factor E2F is linked to the R-point passage. However, stress stimuli trigger exit from the cell cycle back to the mitogen-sensitive quiescent state after Rb hyper-phosphorylation but only until APC/CCdh1 inactivation. In this study, we developed a mathematical model to investigate the reversible transition between quiescence and proliferation in mammalian cells with respect to mitogen and stress signals. The model integrates the current mechanistic knowledge and accounts for the recent experimental observations with cells exiting quiescence and proliferating cells. We show that Cyclin E:Cdk2 couples Rb-E2F and APC/CCdh1 bistable switches and temporally segregates the R-point and the G1/S transition. A redox-dependent mutual antagonism between APC/CCdh1 and its inhibitor Emi1 makes the inactivation of APC/CCdh1 bistable. We show that the levels of Cdk inhibitor (CKI) and mitogen control the reversible transition between quiescence and proliferation. Further, we propose that shifting of the mitogen-induced transcriptional program to G2-phase in proliferating cells might result in an intermediate Cdk2 activity at the mitotic exit and in the immediate inactivation of APC/CCdh1. Our study builds a coherent framework and generates hypotheses that can be further explored by experiments.
Highlights
Tissue homeostasis depends on the ability of mammalian cells to reversibly switch between quiescence (G0) and proliferation
We explored how Cyclin D and Cdk inhibitor (CKI) control the Rb-E2F switch under this circumstance
We found that the inhibition of Cyclin D had no effect from the point when the Cyclin E exceeds CKI levels to sustain Rb hyper-phosphorylation and E2F activation (Fig 2C)
Summary
Tissue homeostasis depends on the ability of mammalian cells to reversibly switch between quiescence (G0) and proliferation. The cycling cells with intermediate Cdk2 activity immediately inactivate APC/CCdh1 and enter the S phase[23]. We show that a rise in Cyclin E:Cdk2 activity (in E2F-dependent manner) initiates APC/CCdh1 inactivation and accumulation of Emi1.
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