DocumentCode :
3490817
Title :
Robustness of CDK2 in triggering cellular senescence based on probability of DNA-damaged cells passing G1/S checkpoint
Author :
Ling, Hong ; Samarasinghe, Sandhya ; Kulasiri, Don
Author_Institution :
Centre for Adv. Comput. Solutions (C-fACS), Lincoln Univ., Christchurch, New Zealand
fYear :
2011
fDate :
2-4 Sept. 2011
Firstpage :
1
Lastpage :
7
Abstract :
Recent experiments have shown that cellular senescence, a mechanism employed by cells for thwarting cell proliferation, plays an important role in protecting cells against cancer; therefore, a deeper understanding of cellular senescence can lead to effective cancer treatment. Inhibition of CDK2 is thought to be the critical trigger for cellular senescence. In this study, we first implement a mathematical model of G1/S transition involving the DNA-damage pathway and show that cellular senescence can be achieved by lowering CDK2. The robustness of CDK2 in triggering cellular senescence is determined from the probability (β) of DNA-damaged cells passing G1/S checkpoint for normal CDK2 and CDK2-deficient situations based on different thresholds of the peak time of two important biomarkers, CycE and E2F. The comparison of the values of β under the normal CDK2 and lower CDK2 levels reveals that reducing CDK2 levels can decrease the percentage of damaged cells passing G1/S checkpoint; more importantly, 50% reduction of CDK2 achieves 65% reduction in the percentage of damaged cells passing the G1/S checkpoint. These results point out that the developed model can highlight the possibility of lowering the bar for cellular senescence by reducing CDK2 levels. The results of investigation of β for the different thresholds of the peak times of other biomarkers show that β is insensitive to these perturbations of the peak time indicating that CDK2 activity is robust in lowering the senescence bar for low and high levels of DNA-damage. Furthermore, a mathematical formulation of robustness indicates that the robustness of CDK2 -triggered senescence increases with decreasing levels of CDK2, and is slightly greater for low-level DNA damage condition.
Keywords :
DNA; cellular biophysics; molecular biophysics; molecular configurations; probability; CDK2 robustness; DNA-damage pathway; DNA-damaged cell probability; G1-S checkpoint; G1-S transition; biomarkers; cellular senescence; perturbations; Biological system modeling; Biomarkers; Cancer; DNA; Kinetic theory; Mathematical model; Robustness; Cancer; Cellular Senescence; G1/S Checkpoint Pathway; Robustness; Systems Biology;
fLanguage :
English
Publisher :
ieee
Conference_Titel :
Systems Biology (ISB), 2011 IEEE International Conference on
Conference_Location :
Zhuhai
Print_ISBN :
978-1-4577-1661-4
Electronic_ISBN :
978-1-4577-1665-2
Type :
conf
DOI :
10.1109/ISB.2011.6033112
Filename :
6033112
Link To Document :
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