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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

Changed timing, duration, and order of signaling events caused by the E2F1-centered long-range negative feedback.The stop of CDKBa_Ubi_E2F1 marks the start of G1. “High Dap” and “High Wee” indicate sDap = 1.0→1.05 and sWee = 1.0→1.8. Numbered arrows indicate events of interest. 1: E2F1 functions for a longer time to activate Stgi into Stga. 2: Fewer CDKE causes a delayed G1. 3: E2F1 needs a longer time to trigger E2F1_Act_CycE in next round. 4: Fewer CDKBa phosphorylates E2F1 for ubiquitination for a shorter period. 5: More accumulated E2F1 quickly triggers E2F1_Act_CycE.
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f3: Changed timing, duration, and order of signaling events caused by the E2F1-centered long-range negative feedback.The stop of CDKBa_Ubi_E2F1 marks the start of G1. “High Dap” and “High Wee” indicate sDap = 1.0→1.05 and sWee = 1.0→1.8. Numbered arrows indicate events of interest. 1: E2F1 functions for a longer time to activate Stgi into Stga. 2: Fewer CDKE causes a delayed G1. 3: E2F1 needs a longer time to trigger E2F1_Act_CycE in next round. 4: Fewer CDKBa phosphorylates E2F1 for ubiquitination for a shorter period. 5: More accumulated E2F1 quickly triggers E2F1_Act_CycE.

Mentions: After the above examinations, we then examined cell cycle phase compensation, an important indication of robustness and adaptiveness of cell cycle control. Reis and Edgar observed that when the G1 Cdk inhibitor Dap is overexpressed, G1/S are elongated, G2/M are shortened, and the total cell cycle length is maintained, and hypothesized that E2F1, which is down regulated by CDKE and CDKB, is the key regulator of cell cycle phase compensation20. To examine this hypothesis, we simulated dap overexpression. When sDap = 1.0→1.05 (“High Dap” in Fig. 3) (sX and dX indicate X’s synthesis and decay rate, respectively), Dap turns more CDKE into the inactive CDKEDap, and fewer CDKE causes a delayed G1 and phosphorylates fewer E2F1 for ubiquitination. Accumulated E2F1 subsequently functions for a longer time to activate Stgi into Stga. Since more Stga quickly activates more CDKBa, the G2/M phases become shortened and CDKBa phosphorylates E2F1 for ubiquitination for a longer period. In the next round, E2F1 needs a longer time to accumulate to the threshold level to activate CycE (Fig. 3).


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

Zhu H, Mao Y - Sci Rep (2015)

Changed timing, duration, and order of signaling events caused by the E2F1-centered long-range negative feedback.The stop of CDKBa_Ubi_E2F1 marks the start of G1. “High Dap” and “High Wee” indicate sDap = 1.0→1.05 and sWee = 1.0→1.8. Numbered arrows indicate events of interest. 1: E2F1 functions for a longer time to activate Stgi into Stga. 2: Fewer CDKE causes a delayed G1. 3: E2F1 needs a longer time to trigger E2F1_Act_CycE in next round. 4: Fewer CDKBa phosphorylates E2F1 for ubiquitination for a shorter period. 5: More accumulated E2F1 quickly triggers E2F1_Act_CycE.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Changed timing, duration, and order of signaling events caused by the E2F1-centered long-range negative feedback.The stop of CDKBa_Ubi_E2F1 marks the start of G1. “High Dap” and “High Wee” indicate sDap = 1.0→1.05 and sWee = 1.0→1.8. Numbered arrows indicate events of interest. 1: E2F1 functions for a longer time to activate Stgi into Stga. 2: Fewer CDKE causes a delayed G1. 3: E2F1 needs a longer time to trigger E2F1_Act_CycE in next round. 4: Fewer CDKBa phosphorylates E2F1 for ubiquitination for a shorter period. 5: More accumulated E2F1 quickly triggers E2F1_Act_CycE.
Mentions: After the above examinations, we then examined cell cycle phase compensation, an important indication of robustness and adaptiveness of cell cycle control. Reis and Edgar observed that when the G1 Cdk inhibitor Dap is overexpressed, G1/S are elongated, G2/M are shortened, and the total cell cycle length is maintained, and hypothesized that E2F1, which is down regulated by CDKE and CDKB, is the key regulator of cell cycle phase compensation20. To examine this hypothesis, we simulated dap overexpression. When sDap = 1.0→1.05 (“High Dap” in Fig. 3) (sX and dX indicate X’s synthesis and decay rate, respectively), Dap turns more CDKE into the inactive CDKEDap, and fewer CDKE causes a delayed G1 and phosphorylates fewer E2F1 for ubiquitination. Accumulated E2F1 subsequently functions for a longer time to activate Stgi into Stga. Since more Stga quickly activates more CDKBa, the G2/M phases become shortened and CDKBa phosphorylates E2F1 for ubiquitination for a longer period. In the next round, E2F1 needs a longer time to accumulate to the threshold level to activate CycE (Fig. 3).

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