A theoretical model for p53 dynamics: identifying optimal therapeutic strategy for its activation and stabilization.
The activation and stabilization of tumor suppressor p53 are very important in preventing cells from becoming cancerous. Hence, many experimental works have been carried out to investigate p53's dynamics through its interactions with other proteins and its therapeutic applications for the treatment of cancers. In this work, by analyzing a theoretical model, we attempt to search for an optimal therapeutic strategy that guarantees the activation and stabilization of p53. For this purpose, we introduce a new mathematical model including oncogene activation and ARF, which are recognized as crucial for tumor suppression but have not yet been considered in most theoretical works. Through mathematical modeling and numerical simulations, we confirm several important properties of p53 dynamics: the role of the oncogene-mediated activation of ARF as an important factor for the activation and stabilization of p53, the necessity of time delays in negative feedback loops to guarantee sustained p53 oscillations, and the digital behavior of p53 pulses. Furthermore, we propose that the binding of ARF to Mdm2 and enhancing the degradation of Mdm2 is an efficient strategy for therapeutic targeting, which may assure the activation and stabilization of p53.
Kim
Do-Hyun
DH
Information Center for Bio-Pharmacological Network, Seoul National University, Suwon, Korea.
Rho
Kyoohyoung
K
Kim
Sunghoon
S
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D064447:Checkpoint Kinase 2; D003198:Computer Simulation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D005786:Gene Expression Regulation / Q000502:physiology* / Q000528:radiation effects; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D009991:Oscillometry; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D011839:Radiation, Ionizing; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism* / Q000627:therapeutic use; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C