Dual roles of SIRT1 in the BAX switch through the P53 module: A mathematical modeling study

Abstract

SIRT1 is a multifunctional deacetylase that participates in a variety of cellular physiological processes to cope with stress. The anticancer protein P53 is an important target of SIRT1. It has been found that SIRT1 is involved in apoptosis by regulating the activity and intracellular location of P53. Moreover, P53-dependent apoptosis is inseparable from the BCL-2 protein family. Among the members of this family, BAX’s switching dynamics may play a key role in apoptosis. Therefore, a challenging question arises: what effect does SIRT1 have on the BAX switch? To answer this question, we built a small-scale protein network model. Through computer simulation, the properties of SIRT1 that on the one hand promote and on the other inhibit apoptosis are revealed. We found that the opening time of the BAX switch will be delayed in the case of either SIRT1 excess or deficiency. Similarly, the stimulus threshold required for apoptosis will also increase in the above two scenarios. Thereby, we proposed that SIRT1 has an optimal content at which the probability of apoptosis is greatest. In addition, P53 oscillation requires the concentration of SIRT1 to be higher than the optimal value. This work may be helpful both experimentally and clinically.

Keywords

• SIRT1
• P53-MDM2
• BAX switch
• Apoptosis
• Bifurcation