Quantifying and mathematical modelling of the influence of soluble adenylate cyclase on cell cycle in human...

Adenosine-3', 5'-cyclic monophosphate (cAMP) produced by adenylate cyclases (ADCYs) is an established key regulator of cell homoeostasis. However, its role in cell cycle control is still controversially discussed. This study focussed on the impact of soluble HCO₃ ^- -activated ADCY10 on cell cycle progression. Effects are quantified with Bayesian inference integrating a mathematical model and experimental data. The activity of ADCY10 in human umbilical vein endothelial cells (HUVECs) was either pharmacologically inhibited by KH7 or endogenously activated by HCO₃ ^- . Cell numbers of individual cell cycle phases were assessed over time using flow cytometry. Based on these numbers, cell cycle dynamics were analysed using a mathematical model. This allowed precise quantification of cell cycle dynamics with model parameters that describe the durations of individual cell cycle phases. Endogenous inactivation of ADCY10 resulted in prolongation of mean cell cycle times (38.7 ± 8.3 h at 0 mM HCO₃ ^- vs 30.3 ± 2.7 h at 24 mM HCO₃ ^- ), while pharmacological inhibition resulted in functional arrest of cell cycle by increasing mean cell cycle time after G₀ /G₁ synchronization to 221.0 ± 96.3 h. All cell cycle phases progressed slower due to ADCY10 inactivation. In particular, the G₁ -S transition was quantitatively the most influenced by ADCY10. In conclusion, the data of the present study show that ADCY10 is a key regulator in cell cycle progression linked specifically to the G₁ -S transition.