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Robustness of cell cycle control and flexible orders of signaling events.

Zhu H, Mao Y - Sci Rep (2015)

Bottom Line: To quantitatively address the two questions, we have developed a novel cell cycle model upon experimental observations.It contains positive and negative E2F proteins and two Cdk inhibitors, and is parameterized, for the first time, to generate not only oscillating protein concentrations but also periodic signaling events.Events and their orders reconstructed under varied conditions indicate that proteolysis of cyclins and Cdk complexes by APC and Skp2 occurs highly robustly in a strict order, but many other events are either dispensable or can occur in flexible orders.

View Article: PubMed Central - PubMed

Affiliation: Bioinformatics Section, School of Basic Medical Sciences, Southern Medical University, Shatai Road, Guangzhou, 510515, China.

ABSTRACT
The highly robust control of cell cycles in eukaryotes enables cells to undergo strictly ordered G1/S/G2/M phases and respond adaptively to regulatory signals; however the nature of the robustness remains obscure. Specifically, it is unclear whether events of signaling should be strictly ordered and whether some events are more robust than others. To quantitatively address the two questions, we have developed a novel cell cycle model upon experimental observations. It contains positive and negative E2F proteins and two Cdk inhibitors, and is parameterized, for the first time, to generate not only oscillating protein concentrations but also periodic signaling events. Events and their orders reconstructed under varied conditions indicate that proteolysis of cyclins and Cdk complexes by APC and Skp2 occurs highly robustly in a strict order, but many other events are either dispensable or can occur in flexible orders. These results suggest that strictly ordered proteolytic events are essential for irreversible cell cycle progression and the robustness of cell cycles copes with flexible orders of signaling events, and unveil a new and important dimension to the robustness of cell cycle control in particular and to biological signaling in general.

No MeSH data available.


Related in: MedlinePlus

Computed protein concentrations and reconstructed signaling events.dX and sX are protein X’s synthesis and decay rates, and aXY is the parameter in a Hill function describing how X activating Y nonlinearly. Each panel’s top and bottom parts show protein concentrations (between 0.0–1.0) and signaling events (indicated by elevated line segments). (A) Under the default parameters all signaling events occur periodically. (B) If the decay rate of active Stg is reduced (dStga = 1.0→0.3) cell cycle is arrested at G1 (not shown); but, if the reduction is accompanied by the removal of Dap from the system by setting the synthesis rate of Dap 0.0 (dStga = 1.0→0.3 & sDap = 1.0→0.0) escape of G1 arrest occurs. (C) If degradation of E2F1 mediated by CDKA occurs earlier (aCDKAE2F1 = 0.14→0.07) cell cycle does not occur, but if this change is accompanied by the removal of Rux (aCDKAE2F1 = 0.14→0.07 & sRux = 1.0→0.0) cell cycles are recovered (see the sharp down of Rux in simulation, proteins different from those in (A) and (B) are marked). (BC) were captured continuously as the parameters changed in simulation (see the sharp down of Dap). In (AB) the wild fluctuations of the first few cycles are caused by the initial conditions and changed parameter, not by noises.
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f2: Computed protein concentrations and reconstructed signaling events.dX and sX are protein X’s synthesis and decay rates, and aXY is the parameter in a Hill function describing how X activating Y nonlinearly. Each panel’s top and bottom parts show protein concentrations (between 0.0–1.0) and signaling events (indicated by elevated line segments). (A) Under the default parameters all signaling events occur periodically. (B) If the decay rate of active Stg is reduced (dStga = 1.0→0.3) cell cycle is arrested at G1 (not shown); but, if the reduction is accompanied by the removal of Dap from the system by setting the synthesis rate of Dap 0.0 (dStga = 1.0→0.3 & sDap = 1.0→0.0) escape of G1 arrest occurs. (C) If degradation of E2F1 mediated by CDKA occurs earlier (aCDKAE2F1 = 0.14→0.07) cell cycle does not occur, but if this change is accompanied by the removal of Rux (aCDKAE2F1 = 0.14→0.07 & sRux = 1.0→0.0) cell cycles are recovered (see the sharp down of Rux in simulation, proteins different from those in (A) and (B) are marked). (BC) were captured continuously as the parameters changed in simulation (see the sharp down of Dap). In (AB) the wild fluctuations of the first few cycles are caused by the initial conditions and changed parameter, not by noises.

Mentions: Molecular interactions are defined in the model and captured in simulations, including A_Act_B (A activates B), A_Ubi_B (A ubiquitinates B), and A_Rep_B (A represses B) (Figs 1 and 2). Upon experimental observations the model was parameterized to first produce oscillating protein concentrations and second to produce periodic signaling events (Fig. 2A; Supplementary Table 1). For most parameters, a large range allows them to generate oscillating protein concentrations, indicating robustness of the model (Supplementary Table 2). The ranges of some E2F2-, Skp2-, E2F1-, and CDKE-related parameters are narrow. To make the model also generate periodic signaling events makes parameters biologically more qualified. Notice that while many parameter settings enable the model to produce oscillating protein concentrations, much fewer enable it to produce all periodic signaling events. Since the start of G1, S, G2, and M phases is featured by the maximal value of APCFzy, the rise of CycA, the rise of CDKBa, and the maximal value of CDKBa, we let the start of G1/S/G2/M be marked by the stop of CDKBa_Ubi_E2F1, the stop of DapE2F2_Rep_CycA and the start of E2F1_Act_CycA, the start of Stga_Rep_CDKBi, and the start of APCFzy_Ubi_CDKBi and APCFzy_Ubi_CDKBa, respectively (Fig. 1).


Robustness of cell cycle control and flexible orders of signaling events.

Zhu H, Mao Y - Sci Rep (2015)

Computed protein concentrations and reconstructed signaling events.dX and sX are protein X’s synthesis and decay rates, and aXY is the parameter in a Hill function describing how X activating Y nonlinearly. Each panel’s top and bottom parts show protein concentrations (between 0.0–1.0) and signaling events (indicated by elevated line segments). (A) Under the default parameters all signaling events occur periodically. (B) If the decay rate of active Stg is reduced (dStga = 1.0→0.3) cell cycle is arrested at G1 (not shown); but, if the reduction is accompanied by the removal of Dap from the system by setting the synthesis rate of Dap 0.0 (dStga = 1.0→0.3 & sDap = 1.0→0.0) escape of G1 arrest occurs. (C) If degradation of E2F1 mediated by CDKA occurs earlier (aCDKAE2F1 = 0.14→0.07) cell cycle does not occur, but if this change is accompanied by the removal of Rux (aCDKAE2F1 = 0.14→0.07 & sRux = 1.0→0.0) cell cycles are recovered (see the sharp down of Rux in simulation, proteins different from those in (A) and (B) are marked). (BC) were captured continuously as the parameters changed in simulation (see the sharp down of Dap). In (AB) the wild fluctuations of the first few cycles are caused by the initial conditions and changed parameter, not by noises.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588580&req=5

f2: Computed protein concentrations and reconstructed signaling events.dX and sX are protein X’s synthesis and decay rates, and aXY is the parameter in a Hill function describing how X activating Y nonlinearly. Each panel’s top and bottom parts show protein concentrations (between 0.0–1.0) and signaling events (indicated by elevated line segments). (A) Under the default parameters all signaling events occur periodically. (B) If the decay rate of active Stg is reduced (dStga = 1.0→0.3) cell cycle is arrested at G1 (not shown); but, if the reduction is accompanied by the removal of Dap from the system by setting the synthesis rate of Dap 0.0 (dStga = 1.0→0.3 & sDap = 1.0→0.0) escape of G1 arrest occurs. (C) If degradation of E2F1 mediated by CDKA occurs earlier (aCDKAE2F1 = 0.14→0.07) cell cycle does not occur, but if this change is accompanied by the removal of Rux (aCDKAE2F1 = 0.14→0.07 & sRux = 1.0→0.0) cell cycles are recovered (see the sharp down of Rux in simulation, proteins different from those in (A) and (B) are marked). (BC) were captured continuously as the parameters changed in simulation (see the sharp down of Dap). In (AB) the wild fluctuations of the first few cycles are caused by the initial conditions and changed parameter, not by noises.
Mentions: Molecular interactions are defined in the model and captured in simulations, including A_Act_B (A activates B), A_Ubi_B (A ubiquitinates B), and A_Rep_B (A represses B) (Figs 1 and 2). Upon experimental observations the model was parameterized to first produce oscillating protein concentrations and second to produce periodic signaling events (Fig. 2A; Supplementary Table 1). For most parameters, a large range allows them to generate oscillating protein concentrations, indicating robustness of the model (Supplementary Table 2). The ranges of some E2F2-, Skp2-, E2F1-, and CDKE-related parameters are narrow. To make the model also generate periodic signaling events makes parameters biologically more qualified. Notice that while many parameter settings enable the model to produce oscillating protein concentrations, much fewer enable it to produce all periodic signaling events. Since the start of G1, S, G2, and M phases is featured by the maximal value of APCFzy, the rise of CycA, the rise of CDKBa, and the maximal value of CDKBa, we let the start of G1/S/G2/M be marked by the stop of CDKBa_Ubi_E2F1, the stop of DapE2F2_Rep_CycA and the start of E2F1_Act_CycA, the start of Stga_Rep_CDKBi, and the start of APCFzy_Ubi_CDKBi and APCFzy_Ubi_CDKBa, respectively (Fig. 1).

Bottom Line: To quantitatively address the two questions, we have developed a novel cell cycle model upon experimental observations.It contains positive and negative E2F proteins and two Cdk inhibitors, and is parameterized, for the first time, to generate not only oscillating protein concentrations but also periodic signaling events.Events and their orders reconstructed under varied conditions indicate that proteolysis of cyclins and Cdk complexes by APC and Skp2 occurs highly robustly in a strict order, but many other events are either dispensable or can occur in flexible orders.

View Article: PubMed Central - PubMed

Affiliation: Bioinformatics Section, School of Basic Medical Sciences, Southern Medical University, Shatai Road, Guangzhou, 510515, China.

ABSTRACT
The highly robust control of cell cycles in eukaryotes enables cells to undergo strictly ordered G1/S/G2/M phases and respond adaptively to regulatory signals; however the nature of the robustness remains obscure. Specifically, it is unclear whether events of signaling should be strictly ordered and whether some events are more robust than others. To quantitatively address the two questions, we have developed a novel cell cycle model upon experimental observations. It contains positive and negative E2F proteins and two Cdk inhibitors, and is parameterized, for the first time, to generate not only oscillating protein concentrations but also periodic signaling events. Events and their orders reconstructed under varied conditions indicate that proteolysis of cyclins and Cdk complexes by APC and Skp2 occurs highly robustly in a strict order, but many other events are either dispensable or can occur in flexible orders. These results suggest that strictly ordered proteolytic events are essential for irreversible cell cycle progression and the robustness of cell cycles copes with flexible orders of signaling events, and unveil a new and important dimension to the robustness of cell cycle control in particular and to biological signaling in general.

No MeSH data available.


Related in: MedlinePlus