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. Author manuscript; available in PMC: 2012 Mar 6.
Published in final edited form as: Nat Rev Cancer. 2011 Jun 16;11(7):523–532. doi: 10.1038/nrc3081

FIGURE 2. Bistable switch controlling the G1-to-S transition in mammalian cells.

FIGURE 2

a | Wiring diagram. Cyclin E-dependent kinase (CycE) promotes the transition of mammalian cells from G1 phase of the cell cycle into S phase. Quiescent cells are arrested in G1 by the retinoblastoma protein (RB), which binds to and inhibits E2F, a family of transcription factors, some of which can promote CYCE gene expression. Phosphorylation of RB by cyclin-dependent kinases compromises its inhibitory effect on E2Fs. The initial phosphorylation of RB is accomplished by cyclin D-dependent kinase (CYCD). After the G1/S transition is made, RB is maintained in its inactive (phosphorylated) form by CYCE and by cyclin A- and B-dependent kinases that are active in S-G2-M. Quiescent cells, which have very little CYCD, can be induced to proliferate by transcription factors (such as Myc, Fos, Jun) that are upregulated by growth factors in serum. These transcription factors promote the expression of both CYCD and E2F genes, and E2F proteins upregulate their own transcription. b | Signal-response curve. The wiring diagram in panel a is converted into a set of nonlinear differential equations (supplementary information S1 (Box)), and the steady-state levels of CYCD and E2F are plotted as functions of serum concentration in the growth medium. Although CYCD level increases smoothly with serum concentration (‘rheostat’), the E2F distribution exhibits a bimodal dependence on serum concentration (‘toggle switch’)41,43. c and d | Experimental verification in rat embryonic fibroblasts (REF 52 cells); from Yao et al.41, used by permission. Red curves: serum concentration is raised from 0 to final percentage. Green curves: serum concentration is raised to 20% for 5 hours, then lowered to final percentage. GFP fluorescence is driven by an E2F promoter (left) or a CYCD promoter (right). Histograms of CYCD expression shift smoothly up-and-down with final serum percentage. E2F histograms show a bimodal dependence on final serum percentage between ~0.2% and 2%. Notice a distinct hysteresis effect in the E2F response: on shifting serum up (red curves), bistability is not observed until serum level exceeds ~1%, but on shifting serum down (green curves), bistability is maintained to serum levels < 0.2%.