title: Post-translational regulation enables robust p53 regulation.
abstract: BACKGROUND
  The tumor suppressor protein p53 plays important roles in DNA damage repair, cell cycle arrest and apoptosis. Due to its critical functions, the level of p53 is tightly regulated by a negative feedback mechanism to increase its tolerance towards fluctuations and disturbances. Interestingly, the p53 level is controlled by post-translational regulation rather than transcriptional regulation in this feedback mechanism.
  
  
  RESULTS
  We analyzed the dynamics of this feedback to understand whether post-translational regulation provides any advantages over transcriptional regulation in regard to disturbance rejection. When a disturbance happens, even though negative feedback reduces the steady-state error, it can cause a system to become less stable and transiently overshoots, which may erroneously trigger downstream reactions. Therefore, the system needs to balance the trade-off between steady-state and transient errors. Feedback control and adaptive estimation theories revealed that post-translational regulation achieves a better trade-off than transcriptional regulation, contributing to a more steady level of p53 under the influence of noise and disturbances. Furthermore, post-translational regulation enables cells to respond more promptly to stress conditions with consistent amplitude. However, for better disturbance rejection, the p53- Mdm2 negative feedback has to pay a price of higher stochastic noise.
  
  
  CONCLUSIONS
  Our analyses suggest that the p53-Mdm2 feedback favors regulatory mechanisms that provide the optimal trade-offs for dynamic control.
authors.affiliation: School of Electrical and Computer Engineering, 402 Phillips Hall, Cornell University, Ithaca, NY 14853, USA. xs66@cornell.edu.
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Shin
authors.forename: Kai-Yuan
authors.initials: KY
authors.lastname: Chen
authors.forename: Ali H
authors.initials: AH
authors.lastname: Sayed
authors.forename: Brandon
authors.initials: B
authors.lastname: Hencey
authors.forename: Xiling
authors.initials: X
authors.lastname: Shen
mesh_terms: D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D008954:Models, Biological; D017711:Nonlinear Dynamics; D011499:Protein Processing, Post-Translational; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D015203:Reproducibility of Results; D013269:Stochastic Processes; D049490:Systems Biology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2